marine drugs Review
Chiral Alkyl Halides: Underexplored Motifs in Medicine Bálint Gál, Cyril Bucher and Noah Z. Burns * Department of Chemistry, Stanford University, 333 Campus Drive, Stanford, CA 94305, USA;
[email protected] (B.G.);
[email protected] (C.B.) * Correspondence:
[email protected]; Tel.: +1-650-723-2961 Academic Editor: Miguel O. Mitchell Received: 24 September 2016; Accepted: 31 October 2016; Published: 4 November 2016
Abstract: While alkyl halides are valuable intermediates in synthetic organic chemistry, their use as bioactive motifs in drug discovery and medicinal chemistry is rare in comparison. This is likely attributable to the common misconception that these compounds are merely non-specific alkylators in biological systems. A number of chlorinated compounds in the pharmaceutical and food industries, as well as a growing number of halogenated marine natural products showing unique bioactivity, illustrate the role that chiral alkyl halides can play in drug discovery. Through a series of case studies, we demonstrate in this review that these motifs can indeed be stable under physiological conditions, and that halogenation can enhance bioactivity through both steric and electronic effects. Our hope is that, by placing such compounds in the minds of the chemical community, they may gain more traction in drug discovery and inspire more synthetic chemists to develop methods for selective halogenation. Keywords: alkyl halide; stereochemistry; lipophilicity; anesthetic; clindamycin; corticosteroid; pimecrolimus; sucralose; halomon; lapachone; astins; forazoline
1. Introduction Alkyl halides are among the most versatile compounds in the chemical industry. Small haloalkanes are some of the most commonly used solvents in chemical laboratories; chlorofluorocarbons have seen widespread use as refrigerants and propellants; and compounds containing both Br and F are often used in fire retardants. Within synthetic organic chemistry, they are commonly used in alkylation reactions, radical cascades, and alkyl cross-coupling chemistry [1–3]. The reactive nature of primary alkyl chlorides is sometimes exploited in medicinal chemistry and chemical biology. HaloTag is a modified haloalkane dehalogenase that is used to covalently bind to a synthetic ligand of choice and fuse to a protein of interest (Figure 1) [4]. This construct allows for a variety of experiments including protein purification, protein stability studies and protein translocation assays. This technology relies on the use of an alkyl chloride linker that rapidly (typically within minutes) forms a covalent bond with the protein tag under physiological conditions. Phenoxybenzamine, an irreversible α-blocker, forms covalent bonds with adrenergic receptors through the attack of a cysteine residue at the alkyl chloride moiety in transmembrane helix 3 (Figure 1) [5]. While primary alkyl halides are often reactive for displacement by nucleophiles, secondary and tertiary chlorides and bromides are significantly less reactive. As a testament to their stability, six drugs on the World Health Organization’s essential medicines list contain such motifs [6].
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Figure 1. The structures of HaloTag and Phenoxybenzamine.
A key consideration in drug development is the pharmacokinetic profile and efficacy of a drug Figure 1. The structures of HaloTag and Phenoxybenzamine. Figure 1. The structures of HaloTag and Phenoxybenzamine. candidate [7]. Halogenation of sp2 carbons is commonly used to increase lipophilicity, which can lead A key consideration in drug development is the pharmacokinetic profile and efficacy of a drug to improved membrane permeability and oral isabsorption [8]. Furthermore, halogenation also A key consideration in drug development the pharmacokinetic profile and efficacy ofcan a drug 2 carbons is commonly used to increase lipophilicity, which can lead candidate [7]. Halogenation of sp enhance the blood–brain barrier permeability, which is crucial for drugs targeting the central nervous 2 candidate [7]. Halogenation of sp carbons is commonly used to increase lipophilicity, which can lead to improved membrane permeability and oral absorption [8]. Furthermore, halogenation can also system [9]. These properties are most often exploited by the introduction of aryl chlorides into drug to improved membrane permeability and oral absorption [8]. Furthermore, halogenation can also enhance the blood–brain barrier permeability, which is crucial for drugs targeting the central nervous candidates [10]. Indeed, approximately a third of the compounds in clinical trials contain these motifs. enhance the blood–brain barrier permeability, which is crucial for drugs targeting the central nervous system [9]. These properties are most often exploited by the introduction of aryl chlorides into drug Intriguingly, alkyl chlorides are only used in a handful of drugs, some of which are described below. system [9]. These properties are most often exploited by the introduction of aryl chlorides into drug candidates [10]. Indeed, approximately a third of the compounds in clinical trials contain these motifs. This review aims to detail some compounds of medicinal significance that contain a halogen‐ candidates [10]. Indeed, approximately a third of the compounds in clinical trials contain these motifs. Intriguingly, alkyl chlorides are only used in a handful of drugs, some of which are described below. bearing stereogenic center. We hope to illustrate the importance of these motifs and the roles they Intriguingly, alkyl chlorides are only used in a handful of drugs, some of which are described below. This review aims to detail some compounds of medicinal significance that contain a halogen‐ play to enhance the biological and pharmacological properties of drugs. Fluorine, due to its small This review aims to detail some compounds of medicinal significance that contain a halogen-bearing bearing stereogenic center. We hope to illustrate the importance of these motifs and the roles they size and high electronegativity, imparts properties on molecules that are unique to this element. As stereogenic center. We hope to illustrate the importance of these motifs and the roles they play to play to enhance the biological and pharmacological properties of drugs. Fluorine, due to its small these effects have been reviewed previously [11], herein we will focus due on alkyl chlorides and enhance the biological and pharmacological properties of drugs. Fluorine, to its small size and size and high electronegativity, imparts properties on molecules that are unique to this element. As bromides. high electronegativity, imparts properties on molecules that are unique to this element. As these effects these effects have been reviewed previously [11], herein we will focus on alkyl chlorides and have been reviewed previously [11], herein we will focus on alkyl chlorides and bromides. bromides. 2. Alkyl Halides in Medicine 2. Alkyl Halides in Medicine 2. Alkyl Halides in Medicine 2.1. Anesthetics 2.1. Anesthetics General anesthetics are agents that can cause reversible loss of consciousness. They have been 2.1. Anesthetics anesthetics aremid‐1800s agents that[12], can however cause reversible loss of consciousness. They have been used General in medicine since the their mechanism of action remains a topic of General anesthetics are agents that can cause reversible loss of consciousness. They have been used in medicine since the mid-1800s [12], however their mechanism of action remains a topic of debate. For decades, the general view was that anesthetics act by nonspecific perturbation of lipid used in For medicine since mid‐1800s [12], that however their mechanism of action remains a topic of debate. decades, thethe general view was anesthetics act by nonspecific perturbation of lipid membranes. This hypothesis has more recently been disproven as a result of a number of findings. debate. For decades, the general view was that anesthetics act by nonspecific perturbation of lipid membranes. This hypothesis has more recently been disproven as a result of a number of findings. Most Most importantly, stereospecific effects have been observed for general anesthetic binding. Two membranes. This hypothesis has more recently been disproven as a result of a number of findings. importantly, stereospecific effects have been observed for general anesthetic binding. Two chiral alkyl chiral alkyl halide anesthetics, isoflurane and halothane, are on the WHO’s list of essential medicines Most importantly, stereospecific effects have for ofgeneral halide anesthetics, isoflurane and halothane, are been on theobserved WHO’s list essentialanesthetic medicinesbinding. (Figure 2)Two [6]. (Figure 2) [6]. chiral alkyl halide anesthetics, isoflurane and halothane, are on the WHO’s list of essential medicines (Figure 2) [6].
Figure 2. The structures of halothane and isoflurane. Figure 2. The structures of halothane and isoflurane.
In 1991, N. P. Franks and W. R. Lieb found that the two optical isomers of isoflurane exhibited Figure 2. The structures of halothane and isoflurane. In 1991, N. P. Franks and W. R. Lieb found that the two optical isomers of isoflurane differential binding to ion channels in identified molluscan central nervous system neurons [13]. The exhibited differential binding to ion channels in identified molluscan central nervous system In 1991, N. P. Franks and W. R. Lieb found that the two optical isomers of isoflurane exhibited (+)‐isomer was roughly twofold more effective than the (−)‐isomer at eliciting the anesthetic‐activated neurons [13]. The (+)-isomer was roughly twofold more effective than the (−)-isomer at eliciting differential binding to ion channels in identified molluscan central nervous system neurons [13]. The potassium current IK(An) at the human median effect dose (ED50) for general anesthesia. Both isomers the anesthetic-activated potassium current IK(An) at the human median effect dose (ED50 ) for general (+)‐isomer was roughly twofold more effective than the (−)‐isomer at eliciting the anesthetic‐activated were found to be equally effective at disrupting lipid bilayers. anesthesia. Both isomers were found to be equally effective at disrupting lipid bilayers. potassium current I K(An) at the human median effect dose (ED 50) for general anesthesia. Both isomers It is now postulated that general anesthetics exert their action through the activation of It is now postulated that general anesthetics exert their action through the activation of inhibitory were found to be equally effective at disrupting lipid bilayers. inhibitory central nervous system (CNS) receptors, and through the inactivation of CNS excitatory central nervous system (CNS) receptors, and through the inactivation of CNS excitatory receptors [12]. It is now postulated that general anesthetics exert their action through the activation of receptors [12]. Recently, a small number of molecular targets have emerged. These include gamma‐ Recently, a small number of molecular targets have emerged. These include gamma-aminobutyric acid inhibitory central nervous system (CNS) receptors, and through the inactivation of CNS excitatory aminobutyric acid type A receptors (GABAA), two pore domain potassium (2PK) channels, and N‐ type A receptors (GABAA ), two pore domain potassium (2PK) channels, and N-methyl-D-aspartate receptors [12]. Recently, a small number of molecular targets have emerged. These include gamma‐ methyl‐D‐aspartate (NMDA) receptors. How anesthetics interact with these targets on a molecular (NMDA) receptors. How anesthetics interact with these targets on a molecular level is also aminobutyric acid type A receptors (GABAA), two pore domain potassium (2PK) channels, and N‐ level is also becoming clearer. becoming clearer. methyl‐D‐aspartate (NMDA) receptors. How anesthetics interact with these targets on a molecular level is also becoming clearer.
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One protein that halogenated anesthetics have been shown to interact with is ferritin, a large 4-helix One protein that halogenated anesthetics have been shown to interact with is ferritin, a large 4‐ bundle protein. In 2005, Liu and coworkers solved the structure of both halothane/ferritin One protein that halogenated anesthetics have been shown to interact with is ferritin, a large 4‐ helix bundle protein. In 2005, Liu and coworkers solved the structure of both halothane/ferritin and and isoflurane/ferritin complexes (Figure 3) [14]. Halothane binds in a hydrophobic cavity between helix bundle protein. In 2005, Liu and coworkers solved the structure of both halothane/ferritin and isoflurane/ferritin complexes (Figure 3) [14]. Halothane binds in a hydrophobic cavity between two two ferritin monomers. While racemic compound was used for this study, the electron density map isoflurane/ferritin complexes (Figure 3) [14]. Halothane binds in a hydrophobic cavity between two ferritin monomers. While compound was used for this this study, the the electron density map ferritin monomers. While racemic racemic compound was used study, electron density map revealed that the (+)-isomer was twice as abundant as for the (−)-isomer. Due to the hydrophobic revealed that the (+)‐isomer was twice as abundant as the (−)‐isomer. Due to the hydrophobic revealed that the (+)‐isomer was twice as abundant as the (−)‐isomer. Due to the hydrophobic environment, the strongest contributors to binding are halogen bonding interactions [15] between environment, the strongest contributors to binding are halogen bonding interactions [15] between the the Brenvironment, the strongest contributors to binding are halogen bonding interactions [15] between the of halothane and ferritin’s carbonyl oxygen at Leu24, as well as a halogen-π contact between Br Br of of halothane and ferritin’s Leu24, as as well well as as a a halogen‐π halogen‐π contact between halothane and ferritin’s carbonyl carbonyl oxygen oxygen at Leu24, contact between halothane’s Cl atom and the aromatic ring in Tyr28 [16], Figure 3. These results very clearly illustrate halothane’s Cl atom and the aromatic ring in Tyr28 [16], Figure 3. These results very clearly illustrate halothane’s Cl atom and the aromatic ring in Tyr28 [16], Figure 3. These results very clearly illustrate that the stereochemistry of alkyl halides matters for binding interactions, and that halogen atoms can that the stereochemistry of alkyl halides matters for binding interactions, and that halogen atoms can that the stereochemistry of alkyl halides matters for binding interactions, and that halogen atoms can provide key binding interactions. provide key binding interactions. provide key binding interactions.
Figure 3. Complex of halothane with apoferritin. The key binding interactions include halogen bonds
Figure 3. Complex of halothane with apoferritin. The key binding interactions include halogen bonds between Br and the carbonyl oxygen of Leu24, and Cl‐π interaction between Cl and Tyr28. Figure 3. Complex of halothane with apoferritin. The key binding interactions include halogen bonds between Br and the carbonyl oxygen of Leu24, and Cl-π interaction between Cl and Tyr28. between Br and the carbonyl oxygen of Leu24, and Cl‐π interaction between Cl and Tyr28. 2.2. Clindamycin
2.2.2.2. Clindamycin Clindamycin Clindamycin is a broad spectrum antibiotic derived semisynthetically from the natural product lincomycin (Figure 4). Clindamycin is used for derived the treatment of a variety of bacterial infections, Clindamycin is a broad spectrum antibiotic semisynthetically from the natural product Clindamycin is a broad spectrum antibiotic derived semisynthetically from the natural product including bone and joint infections, strep throat, pneumonia, and endocarditis [17]. Similarly to lincomycin (Figure 4). Clindamycin is used for the of a variety of bacterial infections, including lincomycin (Figure 4). Clindamycin is used for treatment the treatment of a variety of bacterial infections, macrolide antibiotics, lincomycin and clindamycin inhibit protein synthesis by ribosomal bone and jointbone infections, strepinfections, throat, pneumonia, and endocarditis to macrolide antibiotics, including and joint strep throat, pneumonia, [17]. and Similarly endocarditis [17]. Similarly to translocation—they bind to the 50S rRNA of the large bacterial ribosome subunit [18]. lincomycin and clindamycin inhibit protein by ribosomal translocation—they bind to the 50S macrolide antibiotics, lincomycin and synthesis clindamycin inhibit protein synthesis by ribosomal rRNA of the large bacterial ribosome subunit [18]. translocation—they bind to the 50S rRNA of the large bacterial ribosome subunit [18].
Figure 4. The structures of lincomycin and clindamycin.
Figure 4. The structures of lincomycin and clindamycin. Figure 4. The structures of lincomycin and clindamycin.
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In 1985, Francois Le Goffic investigated structure-activity relationships of lincomycin analogs [19]. TheyMar. Drugs 2016, 14, 206 found that clindamycin is highly active compared to lincomycin against a number of test 4 of 11 organisms, while having lower toxicity levels. A number of derivatives at the 7 position have been In 1985, Francois Le Goffic investigated structure‐activity relationships of lincomycin analogs synthesized and tested (see Table 1). The results indicate that in vivo potency is increased when the [19]. They found that clindamycin is highly active compared to lincomycin against a number of test hydrophilic hydroxyl groups are substituted with chloride or bromide. When the stereochemistry of organisms, while having lower toxicity levels. A number of derivatives at the 7 position have been C7 is swapped, the efficacy is increased. This clearly shows the importance of the stereochemistry synthesized and tested (see Table 1). The results indicate that in vivo potency is increased when the of chiral alkyl halides for biological activity. Interestingly, substituting chlorides with bromides and hydrophilic hydroxyl groups are substituted with chloride or bromide. When the stereochemistry of iodides further increased activity. These results clearly demonstrate that halogenation can enhance C7 is swapped, the efficacy is increased. This clearly shows the importance of the stereochemistry of efficacy in alkyl vivo,halides and that exact stereochemistry can play an important rolewith for bioactivity. chiral for the biological activity. Interestingly, substituting chlorides bromides and iodides further increased activity. These results clearly demonstrate that halogenation can enhance Table 1. Modification of lincomycin at the C-7 site. All results are MIC (mg/L). efficacy in vivo, and that the exact stereochemistry can play an important role for bioactivity. Compound Straph. aureus Str. faecalis Table 1. Modification of lincomycin at the C‐7 site. All results are MIC (mg/L). R1 = Compound OH, R2 = H R1 R=1 = OH, R H, R2 = OH 2 = H R1 = Cl, R2 = H R1 = H, R2 = OH R1 = H, R2 = Cl R1 = Cl, R2 = H R1 = H, R2 = Br R R1 =1 = H, R H, R2 2= = Cl I R1 = H, R2 = Br R1 = H, R2 = I
0.4 Straph. aureus 0.4 1.6 0.8 1.6 0.1 0.8 0.05 0.1 0.05 0.05 0.05
12.5 Str. faecalis 12.5 25 12.5 25 6.2 12.5 6.2 6.2 3.2 6.2 3.2
To better understand these differences between lincomycin and clindamycin on a molecular To better understand these differences between lincomycin and clindamycin on a the molecular level, further studies were conducted to elucidate the binding properties. In 1992, interaction level, further studies were conducted to elucidate the binding properties. In 1992, the interaction of of clindamycin and lincomycin with E. coli 23S ribosomal RNA was investigated by chemical clindamycin with E. affinities coli 23S of ribosomal by were chemical footprinting [20].and Thelincomycin in vitro binding the twoRNA drugswas for investigated the ribosome found to footprinting [20]. The in vitro binding affinities of the two drugs for the ribosome were found to be be roughly the same (Kdiss = 5 µM for lincomycin and 8 µM for clindamycin), even though the exact roughly the same (Kdiss = 5 μM for lincomycin and 8 μM for clindamycin), even though the exact geometries of binding were somewhat different. The structure of a complex between clindamycin and geometries of binding were somewhat different. The structure of a complex between clindamycin the 50S ribosomal subunit of the eubacterium Deinococcus radidurans was solved in 2001 (Figure 5) [21]. and the 50S ribosomal subunit of the eubacterium Deinococcus radidurans was solved in 2001 (Figure The crystal structure revealed no strong interaction with the Cl atom of clindamycin. Instead, the key 5) [21]. The crystal structure revealed no strong interaction with the Cl atom of clindamycin. Instead, binding interactions arise from hydrogen bonding interactions between the hydroxyl groups of the the key binding interactions arise from hydrogen bonding interactions between the hydroxyl groups sugarof moiety and nucleosides. Both of these concluded that the higher of clindamycin the sugar moiety and nucleosides. Both studies of these studies concluded that the activity higher activity of was to not attributable to stronger binding, but to increased lipophilicity. However, alone was clindamycin not attributable stronger binding, but to increased lipophilicity. However, lipophilicity lipophilicity alone cannot explain the activity of C7 stereoisomers. Further research in cannot explain the differential activity ofdifferential C7 stereoisomers. Further research would be instructive would be instructive in elucidating how the chloride stereochemistry exactly bears on bioactivity. elucidating how the chloride stereochemistry exactly bears on bioactivity.
Figure 5. Crystal structure of clindamycin bound to the peptidyl transferase cavity of the 50S subunit. Figure 5. Crystal structure of clindamycin bound to the peptidyl transferase cavity of the 50S subunit. The key binding interactions are provided by the sugar hydroxyl groups. The key binding interactions are provided by the sugar hydroxyl groups.
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2.3.2.3. Corticosteroids Corticosteroids 2.3. Corticosteroids Corticosteroids are among the most widely used drug classes due to their ability to exert Corticosteroids are among the most widely used drug classes due to their ability to exert intense intense biological effects in almost any(Figure organ 6). (Figure 6). often Theythe aredrug oftenof the drug choice biological effects in almost any organ They are choice for oftheir anti‐for Corticosteroids are among the most widely used drug classes due to their ability to exert intense their anti-inflammatory and immunosuppressive [22].the These actfor by binding inflammatory and immunosuppressive properties These steroids act by binding to to biological effects in almost any organ (Figure 6). properties They [22]. are often drug steroids of choice their anti‐ glucocorticoid receptors (GRs), therefore the receptor-binding affinity is a major determinant glucocorticoid receptors (GRs), therefore the receptor‐binding affinity is a major determinant of inflammatory and immunosuppressive properties [22]. These steroids act by binding to of therapeutic potential [23]. (GRs), therefore the receptor‐binding affinity is a major determinant of therapeutic potential [23]. glucocorticoid receptors therapeutic potential [23].
Figure 6. The structures of chlorinated corticosteroids used in medicine. Figure 6. The structures of chlorinated corticosteroids used in medicine. Figure 6. The structures of chlorinated corticosteroids used in medicine.
In the case of mometasone furoate, it was found that there is a dipole–dipole interaction between In the case of mometasone furoate, it was found that there is a dipole–dipole interaction between the C21 Cl and an asparagine residue in the binding pocket AncGR2‐Asn33 that contributes to the In the case of mometasone furoate, it was found that there is a dipole–dipole interaction between the C21 Cl and an asparagine residue in the binding pocket AncGR2-Asn33 that contributes to the high affinity of binding [24]. the C21 Cl and an asparagine residue in the binding pocket AncGR2‐Asn33 that contributes to the high affinity of binding [24]. To correlate other structural features with binding affinity to glucocorticoid receptors, extensive high affinity of binding [24]. To correlate other structuralstudies features withcarried binding affinity glucocorticoid receptors, structure activity relationship were out on this toclass of compounds [25,26]. extensive A key To correlate other structural features with binding affinity to glucocorticoid receptors, extensive structure activity relationship studies were carried out to on 6–7‐fold this classincrease of compounds [25,26]. A key finding was that fluorination or chlorination leads in binding affinity. structure activity relationship studies were carried out on this class of compounds [25,26]. A key finding was that fluorination or chlorination leads to 6–7-fold increase in binding affinity. Interestingly, Interestingly, at the positions leads actually implies a size finding was bromination that fluorination or same chlorination to reduces 6–7‐fold binding, increase which in binding affinity. bromination at the same positions actually binding, implies a sizewhich limitation for effective limitation for effective fit in the binding pocket. The origin of these effects is unknown at this stage, Interestingly, bromination at the same reduces positions actually which reduces binding, implies a size fit further research is needed to understand how halogenation can have such a striking effect on binding in the binding pocket. The origin of these effects is unknown at this stage, further research is needed limitation for effective fit in the binding pocket. The origin of these effects is unknown at this stage, to affinity and in turn drug efficacy. understand how halogenation can have such a striking effect on binding affinity and in turn further research is needed to understand how halogenation can have such a striking effect on binding drug efficacy. affinity and in turn drug efficacy. 2.4. Pimecrolimus 2.4.2.4. Pimecrolimus Pimecrolimus Pimecrolimus and tacrolimus are immunosuppressants used for the topical treatment of atopic Pimecrolimus and They tacrolimus are immunosuppressants used for and the topical of atopic dermatitis (eczema). both bind to the protein macrophilin‐12 inhibit treatment the phosphatase Pimecrolimus and tacrolimus are immunosuppressants used for the topical treatment of atopic calcineurin, resulting in the blockage of T cell activation (Figure 7) [27]. dermatitis (eczema). They both bind to the protein macrophilin-12 and inhibit the phosphatase dermatitis (eczema). They both bind to the protein macrophilin‐12 and inhibit the phosphatase calcineurin, resulting in the blockage of T cell activation (Figure 7) [27]. calcineurin, resulting in the blockage of T cell activation (Figure 7) [27].
Figure 7. The structures of Pimecrolimus and Tacrolimus. Figure 7. The structures of Pimecrolimus and Tacrolimus. Figure 7. The structures of Pimecrolimus and Tacrolimus.
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Despite aa high high degree degree of of similarity similarity in in structure structure and and mechanism mechanism of of action, action, pimecrolimus pimecrolimus and and Despite tacrolimus display characteristic differences in terms of pharmacological profile [28]. As a result of tacrolimus display characteristic differences in terms of pharmacological profile [28]. As a result OH to to Cl Cl substitution, the of OH substitution,pimecrolimus pimecrolimusis isapproximately approximatelyeight eighttimes timesmore more lipophilic lipophilic based based on on the octanol/water distribution = =6.99 0.05 for pimecrolimus vs. vs. 6.09 ± 0.04 for octanol/water distributioncoefficient coefficient (ElogD (ElogDoctoct 6.99± ± 0.05 for pimecrolimus 6.09 ± 0.04 tacrolimus). Consequently, it has a higher affinity to the skin and lower levels of permeation. This for tacrolimus). Consequently, it has a higher affinity to the skin and lower levels of permeation. explains the observed lower systemic exposure to to pimecrolimus topical This explains the observed lower systemic exposure pimecrolimusthan thanto totacrolimus tacrolimus after after topical application. The The unbound unbound fraction pimecrolimus in human plasma was approximately application. fraction of of pimecrolimus in human plasma was approximately 9-fold 9‐fold lower lower compared with that of tacrolimus (0.4 ± 0.1 vs. 3.7 ± 0.8%). compared with that of tacrolimus (0.4% ± 0.1% vs. 3.7% ± 0.8%). 2.5. Sucralose 2.5. Sucralose ® is one of the most common artificial sweeteners and sugar substitutes Sucralose Sucralose (Splenda (Splenda®) ) is one of the most common artificial sweeteners and sugar substitutes (Figure 8) [29]. The majority of ingested sucralose is not metabolized by the body, which makes it (Figure 8) [29]. The majority of ingested sucralose is not metabolized by the body, which makes it safe and also noncaloric [30]. This example in particular emphasizes the metabolic stability of alkyl safe and also noncaloric [30]. This example in particular emphasizes the metabolic stability of alkyl chlorides, when they are are adjacent to other electron-withdrawing heteroatoms (even primary chlorides, especially especially when they adjacent to other electron‐withdrawing heteroatoms (even halides can be stable). primary halides can be stable). Researchers have been investigating the structural requirements for sweetness since the 1960s. Researchers have been investigating the structural requirements for sweetness since the 1960s. While taste sensing is a complex phenomenon, some general rules have been established for which While taste sensing is a complex phenomenon, some general rules have been established for which most sweet-tasting compounds adhere to. Schallenberger and Acree proposed that for a compound most sweet‐tasting compounds adhere to. Schallenberger and Acree proposed that for a compound to be sweet, it needs to possess a hydrogen bond donor, and a Lewis basic site roughly 0.3 nm to be sweet, it needs to possess a hydrogen bond donor, and a Lewis basic site roughly 0.3 nm apart apart [31,32]. For enhanced sweetness compared to sucrose, the importance of a third, hydrophobic, [31,32]. For enhanced sweetness compared to sucrose, the importance of a third, hydrophobic, site site was established [33]. In sucralose, two chlorine atoms present in the fructose portion of the was established [33]. In sucralose, two chlorine atoms present in the fructose portion of the molecule molecule comprise the hydrophobic site. comprise the hydrophobic site. Generally, highly intense sweeteners tend to be more hydrophobic, which is suggested to give Generally, highly intense sweeteners tend to be more hydrophobic, which is suggested to give rise to stronger absorption to taste bud tissue in contrast to simpleto sugars, which are more hydrophilic, rise to stronger absorption to taste bud tissue in contrast simple sugars, which are more less sweet and weakly absorbed to the taste buds. This trend can be clearly observed in the series of hydrophilic, less sweet and weakly absorbed to the taste buds. This trend can be clearly observed in synthetic halogenated analogs of sucrose (Figure 8) [29]. the series of synthetic halogenated analogs of sucrose (Figure 8) [29].
Figure 8. 8. The relative sweetness sweetness of of some some disaccharides disaccharides and and halogenated halogenated derivatives. derivatives. Increased Increased Figure The relative hydrophobicity increases perceived sweetness. hydrophobicity increases perceived sweetness.
3. Alkyl Halide Natural Products 3. Alkyl Halide Natural Products Natural products have always inspired the development of novel medicines, as exhibited by the Natural products have always inspired the development of novel medicines, as exhibited by fact that between 1981 and 2014 approximately 40% of all new approved drugs were based on natural the fact that between 1981 and 2014 approximately 40% of all new approved drugs were based on products [34]. It [34]. is therefore instructive to describe the the biological activity natural products It is therefore instructive to describe biological activityof ofsome some halogenated halogenated secondary metabolites that may serve as drug candidates. It is an interesting historical note that for a secondary metabolites that may serve as drug candidates. It is an interesting historical note that for a long time the chemistry community believed very few halogenated natural products existed. However, recent years have witnessed a surge in the isolation of halogenated molecules from marine
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organisms, counting more than 5000 today [35]. This, in time, could thus translate into a greater Mar. Drugs 2016, 14, 206 number of alkyl chloride and bromide containing drug candidates.
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3.1. Halomon
Mar. Drugs 2016, 14, 206 long time the chemistry community believed very few halogenated natural products existed.
7 of 11 However, recentHalomon (Figure 9) was isolated in 1975 from the red algae Portieria hornemannii [36]. Seventeen years have witnessed a surge in the isolation of halogenated molecules from marine organisms, years later it produced one of the most extreme cases of differential cytotoxicity in a National Cancer organisms, counting more than 5000 today [35]. could This, in time, could into thus translate into a of greater counting more than 5000 today [35]. This, in time, thus translate a greater number alkyl Institute NCI‐60 human tumor cell line screen [37]. The compound was selected for preclinical drug number of alkyl chloride and bromide containing drug candidates. chloride and bromide containing drug candidates. development, but then later was dropped due to lack of material [38]. Even though the detailed 3.1. Halomon 3.1. Halomon mechanism of action is unknown, it has been suggested that the activity is due to the inhibition of DNA methyltransferase, an important target for combatting cancer because of its tendency to Halomon (Figure 9) was isolated in 1975 from the red algae Portieria hornemannii [36]. Seventeen Halomon (Figure 9) was isolated in 1975 from the red algae Portieria hornemannii [36]. Seventeen hypermethylate tumor suppressing regions in tumor suppressing cells [39]. Computational analysis years later it produced one of the most extreme cases of differential cytotoxicity in a National Cancer years later it produced one of the most extreme cases of differential cytotoxicity in a National Cancer of the cytotoxicity profile of halomon has suggested that the activity cannot be attributable to simple Institute NCI‐60 human tumor cell line screen [37]. The compound was selected for preclinical drug Institute NCI-60 human tumor cell line screen [37]. The compound was selected for preclinical drug nonspecific alkylation reactions in the body [40]. Investigations into the mechanism of action of this development, dropped due due to to lack lack of of material material [38]. [38]. Even the detailed detailed development, but but then then later later was was dropped Even though though the molecule are ongoing within our laboratory through collaborations [41]. Initial results suggest that mechanism of action is unknown, it has been suggested that the activity is due to the inhibition of mechanism of action is unknown, it has been suggested that the activity is due to the inhibition the unnatural enantiomer, (−)‐halomon, is inactive against a series of cancers that are sensitive to (+)‐ DNA methyltransferase, an an important target of DNA methyltransferase, important targetfor forcombatting combattingcancer cancerbecause becauseof of its its tendency tendency to to halomon [42]. hypermethylate tumor suppressing regions in tumor suppressing cells [39]. Computational analysis hypermethylate tumor suppressing regions in tumor suppressing cells [39]. Computational analysis of the cytotoxicity profile of halomon has suggested that the activity cannot be attributable to simple of the cytotoxicity profile of halomon has suggested that the activity cannot be attributable to simple nonspecific alkylation reactions in the body [40]. Investigations into the mechanism of action of this nonspecific alkylation reactions in the body [40]. Investigations into the mechanism of action of this molecule are ongoing within our laboratory through collaborations [41]. Initial results suggest that molecule are ongoing within our laboratory through collaborations [41]. Initial results suggest that the unnatural enantiomer, (−)‐halomon, is inactive against a series of cancers that are sensitive to (+)‐ the unnatural enantiomer, (−)-halomon, is inactive against a series of cancers that are sensitive to halomon [42]. (+)-halomon [42].
Figure 9. The structure of (+)‐halomon, a pentahalogenated myrcene derivative.
3.2. Lapachone β‐lapachone is a natural product present in the bark of the lapacho tree, which grows large spectrum of pharmacological predominantly in Brazil (Figure 10). It is endowed with a activities, including antibacterial [43], antifungal [43], and antimalarial [44,45] activities. It is also a Figure 9. The structure of (+)‐halomon, a pentahalogenated myrcene derivative. Figure 9. The structure of (+)-halomon, a pentahalogenated myrcene derivative. potential treatment for prostate and non‐small cell lung cancers that has been evaluated in clinical 3.2. Lapachone trials [46]. 3.2. Lapachone When testing analogs of β‐lapachone, researchers discovered that bromination at the C3 position β‐lapachone is in of the the lapacho lapacho tree, tree, which which grows grows β-lapachone is a a natural natural product product 50present present in the the bark bark of enhances antiplasmoidal activity [45] (IC 2.7 μM vs. 4.1 μM against Plasmodium falciparum, strain predominantly inin Brazil Brazil (Figure is endowed large spectrum of pharmacological predominantly (Figure 10).10). It isIt endowed with awith largea spectrum of pharmacological activities, F 32) and cytotoxicity [47] (IC 50 0.13 μM vs. 0.27 μM against promyelocytic leukemia HL‐60 cell lines, activities, including antibacterial [43], antifungal [43], and antimalarial [44,45] activities. It is also a including antibacterial [43], antifungal [43], and antimalarial [44,45] activities. It is also a potential MTT assay). To date, no study has reported testing of individual enantiomers, nor chlorinated potential treatment for prostate and non‐small cell lung cancers that has been evaluated in clinical treatment for prostate and non-small cell lung cancers that has been evaluated in clinical trials [46]. derivatives. trials [46]. When testing analogs of β‐lapachone, researchers discovered that bromination at the C3 position Me Me Me Me enhances antiplasmoidal activity [45] (IC50 2.7 μM vs. 4.1 μM against Plasmodium falciparum, strain Br O O F 32) and cytotoxicity [47] (IC50 0.13 μM vs. 0.27 μM against promyelocytic leukemia HL‐60 cell lines, MTT assay). To date, no study has reported testing of individual enantiomers, nor chlorinated derivatives. O O O Me Me -lapachone O
O Me Me (±)-3-bromo--lapachone Br O
Figure 10. The structures of β‐lapachone and its more active analog, 3‐bromo‐β‐lapachone. Figure 10. The structures of β-lapachone and its more active analog, 3-bromo-β-lapachone.
3.3. Astins O researchers discovered O that bromination at the C3 position When testing analogs of β-lapachone, O O Astins A–I are a family of cyclic pentapeptides isolated from the medicinal plant Aster tataricus enhances antiplasmoidal activity [45] (IC50 2.7 µM vs. 4.1 µM against Plasmodium falciparum, strain F 32) -lapachone (±)-3-bromo--lapachone (Figure 11). They contain a 16‐membered ring against of several non‐coded leukemia amino acids, including a β,γ‐ and cytotoxicity [47] (IC50 0.13 µM vs. 0.27 µM promyelocytic HL-60 cell lines, MTT dichlorinated proline residue [48]. Their antitumor activity was assayed using Sarcoma 180 ascites in assay). ToFigure 10. The structures of β‐lapachone and its more active analog, 3‐bromo‐β‐lapachone. date, no study has reported testing of individual enantiomers, nor chlorinated derivatives. mice. The effectiveness was evaluated in terms of the tumor growth ratio. At 5 mg/kg/day astins A, 3.3. Astins Astins A–I are a family of cyclic pentapeptides isolated from the medicinal plant Aster tataricus (Figure 11). They contain a 16‐membered ring of several non‐coded amino acids, including a β,γ‐ dichlorinated proline residue [48]. Their antitumor activity was assayed using Sarcoma 180 ascites in mice. The effectiveness was evaluated in terms of the tumor growth ratio. At 5 mg/kg/day astins A,
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3.3. Astins Astins A–I are a family of cyclic pentapeptides isolated from the medicinal plant Aster tataricus (Figure 11). They contain a 16-membered ring of several non-coded amino acids, including a β,γ-dichlorinated proline residue [48]. Their antitumor activity was assayed using Sarcoma 180 ascites Mar. Drugs 2016, 14, 206 8 of 11 in mice. The effectiveness was evaluated in terms of the tumor growth ratio. At 5 mg/kg/day astins A, B and C gave the GR (tumor growth ratio) values of 40%, 26% and 45%, respectively, whereas Mar. Drugs 2016, 14, 206 8 of 11 the B and C gave the GR (tumor growth ratio) values of 40%, 26% and 45%, respectively, whereas the otherother natural astins (F, G, I) and the derivatives of dechlorinated proline residues did not inhibit the natural astins (F, G, I) and the derivatives of dechlorinated proline residues did not inhibit the B and C gave the GR (tumor growth ratio) values of 40%, 26% and 45%, respectively, whereas the tumor growth at 10 mg/kg/day. The presence of cis dechlorinated proline residues was concluded to tumor growth at 10 mg/kg/day. The presence of cis dechlorinated proline residues was concluded to be another natural astins (F, G, I) and the derivatives of dechlorinated proline residues did not inhibit the important structural motif for astins for antitumor activity. be an important structural motif for astins for antitumor activity. tumor growth at 10 mg/kg/day. The presence of cis dechlorinated proline residues was concluded to be an important structural motif for astins for antitumor activity.
Figure 11. The general structure of compounds belonging to the family of astins. Figure 11. The general structure of compounds belonging to the family of astins. Figure 11. The general structure of compounds belonging to the family of astins.
3.4. Forazoline
3.4. Forazoline
Forazoline A was recently isolated from the marine Actinomadura sp. (Figure 12) [49]. It 3.4. Forazoline
Forazoline A was recently isolated from the marine Actinomadura sp. (Figure 12) [49]. It demonstrated demonstrated in vivo antifungal efficacy, comparable to amphotheracin B, against C. albicans. It was Forazoline A was recently isolated from the marine Actinomadura sp. (Figure 12) [49]. It in vivo antifungal comparable amphotheracin B, against C. albicans. It was also found also found to efficacy, be nontoxic in mice. toFurther experiments suggested that forazoline affects cell to be demonstrated in vivo antifungal efficacy, comparable to amphotheracin B, against C. albicans. It was membranes, potentially through the disregulation of phospholipid homeostasis. It is unknown at this nontoxic in mice. Further experiments suggested that forazoline affects cell membranes, potentially also found to be nontoxic in mice. Further experiments suggested that forazoline affects cell stage how much of the biological activity is attributable to the presence of the alkyl chloride moiety. through the disregulation of phospholipid homeostasis. It is unknown at this stage how much of the membranes, potentially through the disregulation of phospholipid homeostasis. It is unknown at this biological activity is attributable to the presence of the alkyl chloride moiety. stage how much of the biological activity is attributable to the presence of the alkyl chloride moiety.
Figure 12. Structure of the recently isolated forazoline A. Figure 12. Structure of the recently isolated forazoline A.
4. Summary and Outlook Figure 12. Structure of the recently isolated forazoline A. This review has aimed to illustrate the medical benefit of chiral alkyl halides, as well as the 4. Summary and Outlook
4. Summary and Outlook features of these compounds that play a key role in their activity. Alkyl halides, especially chlorides, This review has aimed to illustrate the medical benefit of chiral alkyl halides, as well as the are often stable, which is underscored by the number of compounds in the clinic and food industry
features of these compounds that play a key role in their activity. Alkyl halides, especially chlorides, This review has aimed to illustrate the medical benefit of chiral alkyl halides, as well as the containing these motifs. Halogenation, and the stereochemistry of the halogen‐bearing carbons can are often stable, which is underscored by the number of compounds in the clinic and food industry features of these compounds that play a key role in their activity. Alkyl halides, especially chlorides, significantly alter bioactivity. This can happen through increased lipophilicity, which leads to better containing these motifs. Halogenation, and the stereochemistry of the halogen‐bearing carbons can are often stable, which is underscored byhalogen the number compounds in the clinic and food industry pharmacokinetic properties. However, atoms ofcan also play key roles in binding through significantly alter bioactivity. This can happen through increased lipophilicity, which leads to better containing these motifs. Halogenation, the stereochemistry of the halogen-bearing carbons halogen bonding interactions, and, in and a number of cases, the exact roles of halogens are not fully can pharmacokinetic properties. However, halogen atoms can also play key roles in binding through significantly alter bioactivity. This number can happen through increasednatural lipophilicity, which leadswith to better elucidated. Finally, a growing of isolated halogenated products endowed halogen bonding interactions, and, in a number of cases, the exact roles of halogens are not fully unique bioactivity show promise for further Looking it is that through the pharmacokinetic properties. However, halogendevelopment. atoms can also playforward, key roles in clear binding elucidated. Finally, a growing number of isolated halogenated natural products endowed with synthetic community has a huge opportunity for the understanding and prediction of the properties halogen bonding interactions, and, in number of cases, the exact forward, roles of halogens unique bioactivity show promise for afurther development. Looking it is clear are that not the fully of chiral alkyl halides through molecular design. Looking forward, it is also clear that in order to synthetic community has a huge opportunity for the understanding and prediction of the properties better understand and predict the properties of chiral alkyl halides, the synthetic community needs of chiral alkyl halides through molecular design. Looking forward, it is also clear that in order to novel, highly selective methods for their installation. better understand and predict the properties of chiral alkyl halides, the synthetic community needs novel, highly selective methods for their installation.
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elucidated. Finally, a growing number of isolated halogenated natural products endowed with unique bioactivity show promise for further development. Looking forward, it is clear that the synthetic community has a huge opportunity for the understanding and prediction of the properties of chiral alkyl halides through molecular design. Looking forward, it is also clear that in order to better understand and predict the properties of chiral alkyl halides, the synthetic community needs novel, highly selective methods for their installation. Acknowledgments: This work was supported by Stanford University and the National Institutes of Health (R01 GM114061). Conflicts of Interest: The authors declare no conflict of interest.
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