andrographolide

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semi synthesis of anti-cancer agents. Keywords Anti-cancer drugs 4 Natural products 4. Andrographolide 4 Semi-synthetic derivatives. Introduction.
Phytochem Rev DOI 10.1007/s11101-016-9478-9

Anticancer potential of labdane diterpenoid lactone ‘‘andrographolide’’ and its derivatives: a semi-synthetic approach Venu Sharma . Tanwi Sharma . Sanjana Kaul . Kamal K. Kapoor . Manoj K. Dhar

Received: 8 July 2016 / Accepted: 30 August 2016 Ó Springer Science+Business Media Dordrecht 2016

Abstract Natural products have been a great source of pharmaceuticals since ages. Vast screening of natural products from different sources has led to the discovery of plethora of chemotherapeutic drugs and other compounds for the betterment of human life. Several bioactive entities have been generated by the structural modifications of the natural products or by using the natives as key models in synthetic chemistry. Nonetheless, a number of natural compounds with potential bioactivities remain unexploited in the medicinal field due to their stringent chemical properties. Andrographis paniculata Nees., a traditional medicinal herb from family Acanthaceae is known for its multiple pharmacological activities. It’s major bioactive constituent ‘‘andrographolide’’, possesses promising anticancer potential and is one such unexploited treasure. The architecture of the molecule consists of an a-alkylidene c-butyrolactone moiety, two olefin bond [D8(17) and D12(13)], three hydroxyls at C-3, C-19, and C-14 and highly substituted trans decalin. Of the three hydroxyl groups, one is allylic at V. Sharma (&)  T. Sharma  S. Kaul (&)  M. K. Dhar School of Biotechnology, University of Jammu, Jammu, J&K 180006, India e-mail: [email protected] S. Kaul e-mail: [email protected] K. K. Kapoor Department of Chemistry, University of Jammu, Jammu, J&K 180006, India

C-14, and the others are secondary and primary at C-3 and C-19, respectively. By modification of the above structural features a number of andrographolide derivatives have been synthesized. The intricacy of the molecule has always been a constraint in developing a commercialized drug, nevertheless the efforts in this direction via synthetic chemistry are still continuous and prominent. The present review highlights the chemistry and anticancer activity of andrographolide. It discusses the limitations of the molecule as a pharmacological agent. Modifications in the key molecule along different moieties has been discussed which might lead to desirable bioactive molecules. The compiled information will be helpful in further developing specific modifications in andrographolide moiety which will have significant contribution in semi synthesis of anti-cancer agents. Keywords Anti-cancer drugs  Natural products  Andrographolide  Semi-synthetic derivatives

Introduction Natural products are generally regarded as a rich source of components that have found significant applications in the field of pharmacy (De Corte 2016). They are established to be biologically more compatible with human system. Natural compounds or their derived drugs prevent the side effects of synthetic

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drugs (Lahlou 2013). Several products isolated from plants, marine flora and microorganisms possess unique properties like greater number of chiral centers, increased steric complexity, fewer hetero atoms, fewer heavy atoms etc. This accounts for the huge structural diversity of natural products which further results into their rich bioactive potentiality (Kaul et al. 2012; Brusotti et al. 2013). Such metabolites being biologically compatible with the human system have found significant applications in the medicinal field. These bioactive principles can serve as lead compounds for improvement of their therapeutic potential by molecular modification of their functional groups. For increasing the remedial function of these bioactive principles and optimizing pharmacokinetics, attention on significant chemical transformations is needed (Szychowski et al. 2014). Thus, application of synthetic or semi-synthetic chemistry the structural analogues with greater pharmacological activity and fewer side effects can be generated for their successful application in pharmaceutical field (Lahlou 2013; De Corte 2016). The chemotherapeutic drug research from plants started in 1950 with the discovery and development of vinca alkaloids (Varma et al. 2011). Since then, within the sphere of developing anti cancer agents, a number of important natural product inspired drugs have been obtained by their structural modifications. Major phyto-pharmacophores employed in chemotherapy are structurally classified into five major groups viz Vinca alkaloids; Podophyllotoxin derivatives; Taxane diterpenoids; Camptothecin quinoline alkaloids and Homoharringtonine. Vinca alkaloids have been isolated from Catharanthus roseus G. Don. (Apocynaceae). Its semisynthetic analogues with anticancer potential includes vinblastine (velban), vincristine (oncovin), vindesine (eldisine), vinorelbine, vinpocetine (a semisynthetic ethyl ester of apovincamine), desoxyvincaminol, vincaminol, vincamajine, vineridine, vinburnine etc. Similarly, Podophyllotoxin derivatives have been isolated from plants of Podophyllaceae family such as Podophyllum peltatum Linn. and P. emodi Wallich. Epipodophyllotoxin (isomer of podophyllotoxin) lignans, its semi-synthetic derivatives etoposide (Vepesid) and teniposide (Vumon) have established therapeutic use. Taxane diterpenoids have been isolated from Taxus species (Taxaceae) such as T. brevifolia Nutt., and T. baccata. 10-Deacetyl-baccatin

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III is one of the major phyto-constituents from the leaves of Taxus baccata. Paclitaxel (taxol) and docetaxel (taxotere) have been semi-synthesized from this compound. Docetaxel has better pharmacokinetic properties, such as better water solubility than taxol. Camptothecin quinoline alkaloids have been isolated from Camptotheca acuminata Decne (Nyssaceae). Topotecan and irinotecan are more effective derivatives of native camptothecin (5). Similarly, Homoharringtonine has been isolated from Cephalotaxus harringtonia; Elliptinium, a derivative of ellipticine from Bleekeria vitensis; flavopiridol, a synthetic flavone structurally based on alkaloid rohitukine from Amoora rohituka and Dysoxylum binectarium. Combretastatins, 4-ipomeanol, colchicines, genistein, lapachol and curcumin are also very promising natural compounds and their derivatives have been found to possess reputed anti-cancer properties (Pan et al. 2013; Prakash et al. 2013). A number of wonderful therapeutic active molecules may be explored by collecting ethnobotanical, ethnopharmaceutical, ethnomedicinal information and by folkloric survey. In the field of prospective anticancer agents, a large number of natural products still need to be discovered. The present review focuses on the anticancer potential of ‘‘andrographolide’’, the major bioactive constituent of Andrographis paniculata Nees. We have tried to reassemble the semisynthetic work done by different groups on this wonderful molecule leading to its modification so as to enhance its biological activity towards better pharmacological properties. The present review compiles information that will be helpful for developing specific modifications in andrographolide moiety which will have significant contribution in semi synthesizing the anti-cancer agents. Andrographis paniculata Nees. is a traditional medicinal herb, commonly known as Kalmegh and King of bitters. It belongs to the family Acanthaceae (Table 1). It is a well-known plant of Ayurveda in Indian traditional medicine and also finds place in traditional Chinese medicine. It grows widely in many Asian countries such as China, India, Thailand and Sri Lanka and has a long history of therapeutic usage in Indian and Oriental medicine. In Indian Pharmacopoeia it is used as a predominant constituent of at least 26 Ayurvedic formulations, mainly used in liver disorders (Khare 2007). In ancient Ayurvedic literature this herb is mentioned to be useful in the treatment

Phytochem Rev

14-acetylandrographolide [8] and 19-o-acetylanhydroandrographolide [9] (Fig. 1).

Table 1 Taxonomic hierarchy of Andrographis paniculata Nees Taxonomic divisions

Classification

Kingdom

Plantae

Division

Angiospermae

Class

Dicotyledoneae

Order

Tubiflorae

Family

Acanthaceae

Genus

Andrographis

Species

paniculata Nees.

Andrographolide Andrographolide the major bioactive constituent of A. paniculata is mainly concentrated in the leaves and can be easily isolated from the crude plant extract as crystalline solid (Rajani et al. 2000). It was first isolated by Gorter (1911), and was characterized as trihydroxy lactone (Gorter 1911; Lomlim et al. 2003). Other sources of the main bitter principle are Holmskioldia sanguine Retz (Verbinaceae) and Swertia pseudochinensis (Gentianaceae) (Chaudhuri et al. 1999; Yu et al. 2013).

of neoplasm (Balachandran and Govindarajan 2005). A. paniculata has been reported as a cold property herb in traditional Chinese medicines where it is used to get rid of body heat and to expel body toxins. The plant is particularly known for its extremely bitter properties and is used traditionally as a remedy against common cold, dysentery, fever, tonsillitis, diarrhea, liver diseases, inflammation, herpes and so forth (Zhang and Tan 2000; Panossian et al. 2002; Mishra et al. 2007; Patarapanich et al. 2007; Chao and Lin 2012). A number of bioactive compounds have been reported from the plant, which mainly include diterpene lactones, flavonoids and polyphenols (Rajani et al. 2000; Koteswara et al. 2004; Li et al. 2007; Chao and Lin 2010; Zhou et al. 2010). However, the prime constituent andrographolide [1] has been mainly attributed for its therapeutic properties. Some other labdane diterpines, isolated from A. paniculata are neoandrographolide [2], 14-deoxyandrographolide [3], 14-deoxy-11,12-didehydroandrographolide [4], 14-deoxy-14,15-didehydroandrographolide [5], andrograpanin [6], isoandrographolide [7],

O 14

O

16

O

HO

Andrographolide is a diterpenoid lactone. Chemical properties of the compound have been listed in Table 2. Stereochemistry of this interesting molecule was established by Cava and his collaborators (Cava et al. 1962). Structure of the compound has been elucidated by X-ray crystallographic analysis, molecular stereochemistry, bond distances, bond angles, and so forth (Smith et al. 1982). Pelletier et al. (1968) synthesized the racemic a,bunsaturated lactone [c], which is also obtained through the product (di-acetoxy-keto acid [b]) from ozonolysis of triacetyl andrographolide [a] (Fig. 2). This observation was a confirmation for andrographolide biosynthesis, structure and relative stereochemistry of rings (Pelletier et al. 1968). Andrographolide is chemically designated as (3-[2-[decahydro-6-hydroxy-5-(hydroxymethyl)-5, 8adimethyl-2-methylene-1-napthalenyl] ethylidene] dihydro-4-hydroxy-2(3H)-furanone). It exhibits extraordinarily vast range of biological activities.

O

O

O

O

O

O

O

O

O O

Chemistry of andrographolide

O

O OAc

O

O

O

12

H HO

20 17

1 3

HO

9 7

5 H

18 19

H

OH

Oglc

1

2

HO

HO

H OH

H

OH 3

HO

4

Fig. 1 Major bioactive chemical constituents of Andrographis paniculata Nees.: 1 andrographolide; 2 neoandrographolide; 3 14-deoxyandrographolide; 4 14-deoxy-11,12-didehydroandro

H

H

5

HO H OH

OH

OH 6

7

HO

H OH 8

HO

H

OAc 9

grapholide; 5 14-deoxy-14,15-didehydroandrographolide; 6 andrograpanin; 7 isoandrographolide; 8 14-acetylandrographolide; 9 19-o-acetylanhydroandrographolide

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protective, immunostimulative, hepatoprotective, anti-diabetic, anti-inflammatory, anti-obesity, antioxidant, antipyretic, antidiarrhoeal, anti-leishmanial, anti-fertility, cholerectic, anti-allergic, antibacterial, antifungal, antiviral etc. (Puri et al. 1993; Chao and Lin 2012; Aromdee 2014). The therapeutic use of A. paniculata plant extracts in traditional medicines includes treatment of fever, upper respiratory tract infection, tonsillitis, common cold, pharyngitis, laryngitis, inflammation, pneumonia, pyelonephritis, tuberculosis, hepatic disorders etc. Further, specific research towards biological activities of the phytoconstituent, ‘‘andrographolide’’, has uncovered its important therapeutic role in diseases like hepatotoxicity, intestinal disorders, cardiovascular disorders, respiratory and nervous disorders, cancer, HIV, leishmaniasis, allergies, hyperglycemia etc. Also, it is recognized as a safe molecule on the basis of toxicological studies conducted on animal models (Kumar et al. 2013; Thakur et al. 2015). Studies regarding screening of the phytochemicals for more bioactivities and the mode of action are still being added to increase its potential in pharmaceutical industry.

Table 2 Chemistry of Andrographolide Properties

Andrographolide

Chemical formula

C20H30O5

Molecular weight

350.45 g/M

Melting point

231.32 °C

Boiling point

557 °C

PKa

12.5

Half life

6.6 h

Mean residence time

10.0 h

IUPAC name

3-[2-[Decahydro-6-hydroxy-5(hydroxymethyl)-5,8a-dimethyl-2methylene-1napthalenyl]ethylidene]dihydro-4hydroxy-2(3H)-furanone

Solubility

Ethanol (0.2 mg/ml), DMSO (3 mg/ml), DMF (14 mg/ml)

Nature

White crystalline solid

Structure

O 14

16

O

HO 12 20 1 3

HO

17 9 7

5 H

18 19

OH

Andrographolide as an anticancer agent Andrographolide as a bioactive agent Diverse pharmacological properties of andrographolide have been reported and many of them are still being added continuously to the therapeutic arsenal of the compound. The medicinal properties of this compound have been found cited in Ayurveda, Unani, Sidhha, and traditional Chinese medicinal system. It exhibits various bioactivities such as antitumor, anti-HIV, antigenotoxic, pro-apoptotic, cardio-

Fig. 2 Synthesis of a,bunsaturated lactone [c] through di-acetoxy-keto acid [b] from ozonolysis of triacetyl andrographolide [a]

Anticancer agents with inhibition potential for multiple procancer events are of greater interest for the pharmaceutical research industry, since such molecules are likely to inhibit a wider range of cancer cells. In this context, andrographolide molecule can be considered as a potential candidate for cancer therapeutics research. The compound exhibits cytotoxic property that has been attributed to its antioxidant, antiproliferative and proapoptotic activity. A. paniculata along with its parent compound andrographolide, also produces some of its

O O

AcO

Ozonolysis

AcO

123

H

a

O

O AcO

AcO

O

COOH

H

AcO

H OAc

AcO

b

c

Phytochem Rev

analogues like 14-deoxyandrographolide, 14-deoxy11,12-didehydroandrographolide, isoandrographolide etc. (Kumar et al. 2004; Chen et al. 2008). Interestingly, andrographolide is the most potent one in terms of anticancer activity. Cytotoxic activity of the compound has been reported against various cancer cell lines viz human leukaemia cell line HL-60, breast cancer cell lines MCF-7 and TD-47, colon cancer cell line HT-29 and Col2, human lung cancer cell line LU1 and many more (Satyanarayana et al. 2004; Harjotaruno et al. 2007). In vivo studies also yielded positive results in favour of anticancer potential of andrographolide. Manoharan et al. (2012) have reported the potential of andrographolide towards chemoprevention of 7,12dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Sheeja et al. (2006), Sheeja and Kuttan (2007) have revealed a potent synergistic effect of andrographolide to other chemotherapeutic agents. Andrographolide has been reported to increase the sensitivity of cancer cells towards another chemotherapeutic agent i.e. doxorubicin. Yang et al. (2009) studied synergistic apoptosis induced by the addition of andrographolide to 5-fluorouracil.

Mode of anticancer activity of andrographolide Although, andrographolide has been shown to have anticancer activity, however, its role as an anticancer agent in humans and its molecular mechanism of action has not been fully elucidated. Studies have been conducted on the cytotoxic mode of action of the andrographolide molecule against cancer cell lines. According to Maiti et al. (2006) it leads to cell cycle arrest at G0/G1 phase by increasing the level of cell cycle inhibitory protein p27 and decreasing expression of cyclin dependent Kinase 4 (CDK4). Andrographolide has also been found to inhibit the activity of DNA Topoisomerase II, which is an important enzyme involved in DNA replication (Harjotaruno et al. 2007). Satyanarayana et al. (2004), reported, andrographolide induced inhibition of cell cycle in human breast cancer cell MCF-7. They indicated that andrographolide and its semisynthetic analog DRF 3188 treated MCF cells were blocked in the G0–G1 phase of the cell cycle. Induction of cell-cycle inhibitory protein p27 decreases expression of cyclin-dependent kinase. Thus, the cell cycle inhibition potential of andrographolide might be responsible

towards its cytotoxicity via DNA fragmentation and induction of apoptosis. Their results demonstrated that andrographolide and its novel semisynthetic analog have a similar effect on the cell cycle both in vitro and in vivo. Kim et al. (2005) have demonstrated that Andrographolide induced cell death was achieved through the apoptotic pathway, via the activation of an extrinsic caspase cascade. It has also been reported that the molecule suppressed the activation of NF-jB in stimulate endothelial cells, which reduces the expression of the cell adhesion molecule E-selectin and prevents E-selectin-mediated leukocyte adhesion under flow (Xia et al. 2004). E-selectin is considered to play an important role in hematogenous metastasis. Jiang et al. (2007) have also reported that andrographolide blocks the expression of E-selection, thereby inhibiting the adhesion of cancer cells to the active endothelium. It has also been found to be involved in down-regulation of matrix metalloproteinases-7 (MMP-7) expression, involving PI3 K/Akt signaling pathway resulting in inhibition of angiogenesis for tumor metastasis (Shi et al. 2009; Lee et al. 2010). The inhibition of Janus tyrosine kinases–signal transducers and activators of transcription, phosphatidylinositol 3-kinase and NF-jB signalling pathways, suppression of heat shock protein 90, cyclins and cyclin-dependent kinases, metalloproteinases and growth factors, and the induction of tumour suppressor proteins p53 and p21 are also included in the anticancer mechanisms of andrographolide. These factors lead to inhibition of cancer cell proliferation, survival, metastasis and angiogenesis (Lim et al. 2012). Wong and Hui (2016) have also elucidated the mechanisms of antiproliferative and apoptogenic effects and antitumor efficacy of SRJ09 (3,19-(2bromobenzylidene) andrographolide), a semisynthetic andrographolide derivative.

Pharmacokinetics of andrographolide Kan Jang tablets are the most widely tested product for the pharmacokinetic study of andrographolide. These tablets have a fixed combination of A. paniculata extract comprising of andrographolide (Panossian et al. 2002). Panossian et al. (2000) studied the method to determine the right dose regime and measure the rate of absorption, distribution and

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elimination of andrographolide. To reveal any antiplatelet activating factor effect, the calculated steady state plasma concentration of andrographolide for multiple doses of Kan Jang was found approximately 660 ng/ml i.e. approximate 1.9 lM. The normal therapeutic dose regimen is 3–4 tablets/day i.e. about 1 mg andrographolide/kg/day. At this dose the concentration of andrographolide in blood is about 1342 ng/ml i.e. approx, 3.8 lM. Andrographolide has a high affinity for human serum albumin and 61.2 % of it is bound to serum proteins, 40 % of it can be absorbed into the tissues and blood cells of the organism. Less than 10 % is eliminated via renal elimination. Elimination rate of andrographolide is increased at higher doses of A. paniculata extract (Panossian et al. 2000; Suo et al. 2007). Although, andrographolide has been reported nontoxic but side effects like nausea, vomiting and loss of apetite have been reported due to over dose of the compound. As per citations in the Botanical safety handbook, A. paniculata herb cannot be taken during pregnancy.

Limitations of the molecule as pharmacological agent However, despite its impressive biological activities, the major drawback of andrographolide is poor water solubility making it troublesome to generate formulations for clinical use. Moreover, lipid solubility of the molecule is also poor. Therefore, various semisynthetic analogues are being generated and evaluated in order to find out a better lead.

Derivatives of andrographolide and their cytotoxic activity Andrographolide has an interesting architecture consisting of an a-alkylidene c-butyrolactone moiety, two olefin bond [D8(17) and D12(13)], three hydroxyls at C-3, C-19, and C-14 and highly substituted trans decalin. Of the three hydroxyl groups, one is allylic at C-14, and the others are secondary and primary at C-3 and C-19, respectively. A number of andrographolide derivatives have been synthesized by the modification of the above structural features. Nanduri et al. (2004a, b) synthesized different derivatives of andrographolide by modification of the

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above mentioned functional moieties, and revealed that anticancer activity of andrographolide is retained in 8,17-epoxy andrographolide. While the other derivatives such as 14-deoxy, 12,13-dihydro moiety and andrographolic acid (by lactone ring opening) were found to be less effective. It has been concluded that the intact a-alkylidene c-butyrolactone ring, the D12(13) double bond, C-14 hydroxyl or its ester moiety and D8(17) double bond or epoxy moiety are responsible for cytotoxic activity (Nanduri et al. 2004a, b).

Modifications at three hydroxyl groups Several research groups have derivatized the three hydroxyl groups to generate bioactive ester derivatives (Table 3). For 1,3-diol protection [C-3, C-19 hydroxyl groups] alkylidenes are being formed via acetals or ketals in presence of mild acid catalysts like pyridinium p-toluenesulfonate [PPTS]/p-toluenesulfhonic acid [PTSA]. Devendar et al. (2015) generated a series of 3,19-O acetal derivatives via protecting 1,3-diol with alcohols in presence of cerric ammonium nitrate (CAN). Screening for anticancer activity and ADME evaluation studies of derived compounds; 3,19-O-ethylidene andrographolide, 14-acetyl-3,19O-ethylideneandrographolide, 8,17-epoxy-3,19-Oethylidene andrographolide, and 14-acetyl-8,17epoxy-3,19-O-ethylideneandrographolide were found to be more effective. Jada et al. (2006, 2007, 2008) screened the semi-synthesized andrographolide derivatives against a panel of 60 human cancer cell lines. The results showed that 3,19 isoproplylidene andrographolide was selective towards leukaemia and colon cancer cells, whereas 14-acetyl andrographolide was selective towards leukemia, ovarian and renal cancer cells. The benzylidene derivatives of andrographolide showed more potent anti cancer activities than andrographolide. Sirion et al. (2012) reported a significant high activity of the C-19-silyl and tritylanalogues of andrographolide. Preet et al. (2014) synthesized C-14 ester analogues of andrographolide and their a and b diastereomeric epoxy derivatives. The analogues; andrographolide-14a-O-bromoacetate, andrographolide-14a-O-iodoacetate and andrographolide-8,17-b-epoxide-14a-O-iodoacetate were found to exert significant cytotoxicity in cancer cells, low toxicity towards normal cells and more potency than andrographolide. Peng et al. (2015) confirmed

Phytochem Rev Table 3 Anticancer potential of andrographolide and its derivatives against different cell lines Parent compound

Activity against cancer cell lines (GI50 lM)

Structure O

1. Andrographolide

Breast, CNS, colon, lung, ovarian, prostate and renal

O

HO

GI50 (3–30) (Nanduri et al. 2004a, b)

HO

H OH

1a Andrographolide

Modification target

Derivative compounds O

2. a-Alkylidene c-butyrolactone moiety (Nanduri et al. 2004a, b) HO

Prostate DU145

O

HO

Activity against cancer cell lines [IC50/ GI50/ED50 (lM)] GI50 (2.0)

H OH

2a OH

OH O

HO

Ovarian SK OV3 GI50 (4.0)

17

HO

H OH

2b Andrographolic acid

3. a-Alkylidene c-butyrolactone moiety and C3-OH, C19-OH groups (Luo et al. 2015; Nanduri et al. 2004a, b)

O

Human bladder (NTUB1), Cis-platinresistant human bladder (NP14), Breast cancer (MCF-7, M231)

Cl2HCOCO Cl2HCOCO

IC50 (2.64–22.92)

3a O

NTUB1, MCF-7, M231, NP14

O

IC50 (6.37–14.31)

OAc

AcO TrO

3b

Prostate cancer (DU-145) MeO

OMe

IC50 (0.17)

OH

HO HO

3c O

Prostate cancer (DU-145) NH

N

NH2

IC50 (0.2)

O O

3d F

Breast cancer (MCF-7/ADR) IC50 (4.0)

HO HO

3e

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Phytochem Rev Table 3 continued Parent compound

Activity against cancer cell lines (GI50 lM)

Structure O

4. C-3, C-14, C-19 OH groups (Sirion et al. 2012; Devendar et al. 2015)

Murine leukemia (P-388)

16

14

R1O

O

ED50 (0.34)

12 20

17

9

1 3

R2O

Rat glioma (ASK) ED50 (1.22)

7

18

19

H OR3

4a: R1 = R2 = Ac, R3 = TBS 4b: R1 = R2 = H, R3 = CPh3

Human lung (Lu-1) ED50 (2.92) ED50 P-388: 0.45 ASK: 2.86 Lu-1: 0.88

O

HO

O

O

O

HO H

Renal carcinoma (ICE-6, ACHN)

O

Mouse melanoma (B-16)

H

O

O

O

H

O

H

4c

4d

O

O

O

O

O

O O

O

H

Human lung adeno-carcinoma epithelial (A549) IC50 4c: 2.43–6.34

H O

O

O

O

H

Human cervical (HeLa)

H

4e

4d: 4.34–6.97 4e: 3.34–7.23

O

4f

4f: 4.37–14.51

4c: 3,19-O-ethylideneandrographolide 4d: 8,17-epoxy-3,19-Oethylideneandrographolide 4e: 14-acetyl-3,19-Oethylideneandrographolide 4f: 14-acetyl-8,17-epoxy-3,19-Oethylideneandrographolide 5. OH groups and conjugated olefinic bond (Xu et al. 2006; Wei et al. 2013; Preet et al. 2014)

O

IC50

O

Nasopharyngeal carcinoma cell line (CNE): 64.7 HO

H OH

Esophageal carcinoma (Eca109): 31.9

5a O O

CNE: 64.5 Eca109: 42.2

O O P O Cl

H

5b

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Phytochem Rev Table 3 continued Parent compound

Activity against cancer cell lines (GI50 lM)

Structure O

Human alveolar epithelial cell line (A549),

O

Prostate (DU145), R1O

Nasopharyngeal epidermoid cell line (KB), Vincristin resistant nasopharyngeal cancer cell (lKB-Vin)

H R2 O

R1=R2 = O

O

N N

N

5c

GI50 5c: [30

O

5d

N

5e

5d: A549; 4.87 ± 0.99, DU145; 8.63 ± 0.83, KB; 8.24 ± 0.60, KB-Vin; 9.19 ± 0.55 5e: A549; 1.46 ± 0.25, DU145; 2.27 ± 0.49, KB; 2.55 ± 0.27, KB-Vin; 3.00 ± 0.16

O

6. C-14 OH group (allylic hydroxyl) (Das et al. 2010; Jada et al. 2007)

16

14

R1O

IC50

O

Human leukemic cell lines

12 20

R2O

18

17

9

1 3

U937 (12.87), THP1 (6.69)

7

H OR3

19

6a: R1 = HOOC–(CH2)2CO– R2 = R3 = H

U937 (5.47), THP1 (5.84)

6b: R1 = HOOC–(CH2)3CO–

U937 (9.76), THP1 (7.53)

R2 = R3 = H 6c: R1 = HO2C–CH=CH–CO–

U937 (9.72), THP1 (7.77)

R2 = R3 = H 6d: R1 = HO2C–CH=CH–CH=CH– CO–

U937 (6.27), THP1 (5.68)

R2 = R3 = H 6e: R1 = Ac, R2 = R3 = H

GI50 Human breast cancer(MCF-7): 5.9 ± 1.5, colon (HCT-116): 5.1 ± 2.3

O

O X

GI50

O

O

HEK-293 cells: 8–12 lM MCF-7 cells: 6–8.4 lM

HO HO

6f: X = Br; Andrographolide-14aO-bromoacetate 6g: X = I; Andrographolide-14a-Oiodoacetate O

O I

O

O

O HO HO

6h: Andrographolide-8,17-bepoxide-14a-O-iodoacetate

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Phytochem Rev Table 3 continued Parent compound

Activity against cancer cell lines (GI50 lM)

Structure O

7. C-14 OH and conjugated olefinic bond (Nanduri et al. 2004a, b)

GI50

O

Ovarian SK OV3 (0.18) HO

H OH

7a O

Prostate DU145 (2.0)

O

HO

H OH

7b O

8. C-13 and C-19 OH group (1,3-diol) (Jada et al. 2008)

O

HO

O Ar

GI50 8a: Leukamia (RPMI-8226) 0.02 HL-60(TB): 4.89

O

Benzylidine derivatives

8b: BreastCancer MCF-7: 1.23 Colon Cancer HCT-116: 1.99

Br

Br

8a

8b

8c: Prostate Cancer PC-3: 0.4 DU-145; 3.31

F Cl

8c O

9. C8 = C17 (exocyclic double bond) and OH groups (Nanduri et al. 2004a, b)

GI50 value O

R1O

Ovarian SK OV3 (4.0)

O R2O R3O

H

9a: R1 = R2 = R3 = H 9b: R1 = R2 = R3 = COCH3

GI50 Renal A498 (0.25), Colon SW 620 (1), CNS U 251 and Ovarian SK OV3(2.5)

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9c: R1 = R2 = R3 = COCH2CH3

Ovarian SK OV3 (1.36), Colon SW 620 (2)

9d: R1 = COCH=CH–C6H5 R2 = R3 = H

Colon SW 620 (0.5), Breast MCF7/ADR (2)

9e: R1 = COCH=CH–C6H5 R2 = R3 = COCH2CH3

Breast MCF7/ADR (0.08), Colon SW 620 (2.5)

9f: R1 = COCH=CH–(4-OCH3)C6H4 R2 = R3 = COCH2CH3 9g: R1 = COCH=CH–(3,4-diOCH3)C6H3 R2 = R3 = COCH2CH3

Colon SW 620 (0.6), ovarian SK OV3 and Prostate DU 145 (2) Colon SW 620 (0.4), Breast MCF7/ADR (1.5)

9h: R1 = COCH=CH-(3,4OCH2O)C6H3 R2 = R3 = COCH2CH3

Ovarian SK OV3 (0.3)

Phytochem Rev Table 3 continued Parent compound

Activity against cancer cell lines (GI50 lM)

Structure O

10. OH groups and C12 (olifenic C) (Kasemsuk et al. 2013)

(ED50) O

OMe

NH

OMe OAc TBSO

Leukemia P-388; 0.47 ASK (Atlantic Salmon Kidney) Cell line; 0.77

10a

TBS; Tertbutyldimethylsilyl 11. C12 = C13 (1,3-dipolar cycloaddition) (Hazra et al. 2013)

O

R3

R2 O ON

IC50 R1

N

HO

HepG-2 HeLa, A431, MCF-7, Caco-2, MDCK cell lines R1 = Me, R2 = H, R3 = Me; 7.3–15.4

HO OH

11a O HO

R2 OON N

R3

([50) R1

HO OH

11b

that 14-b-isomeric derivatives have potent activity compared to that of 14-a-isomers of andrographolide. Song et al. (2015) synthesized a series of indolo[3,2b]andrographolide derivatives and revealed that compounds with acetyl group have better activity than those with benzoyl group. 14-Deoxy-14,15-didehydro indole [3,2-b] andrographolide derivatives display stronger toxicity than their corresponding compounds with C-14-hydroxyl free, etherified or esterified compounds. Satyanarayana et al. (2004) reported a semisynthetic analogue of andrographolide DRF3188, showing anti-cancer activity at a lower dosage than andrographolide through a similar mechanism. The synthetic andrographolide-based compounds possess diverse cytotoxic activities with a variety of substitutions. Chen et al. (2013) synthesized andrographolide-19oic acid analogues by selective oxidation of primary hydroxyl group at C-19 position with 2,2,6,6-tetramethylpiperidinyloxy(TEMPO)-N-chlorosuccinamide (NCS) system. They reported that the compounds with benzyl ester group displayed a better cytotoxic activity than those with methyl ester group. Acetylation of C-3 hydroxy group was found unfavorable to the activity

against MCF-7, while favorable to the activity against HCT-116. Wei et al. (2013) modified 14-dehydroxy11,12-didehydro andrographolide to C-3 and C-19 diesters and found them having better cytotoxic activity than their monoester congeners. Modifications at D12(13) double bond The electron deficient double bond between C-12 and C-13 is reported to be crucial for cytotoxicity, possibly due to its ability to promote alkylation of biological nucleophiles such as enzyme, through Michael addition (Das et al. 2010). To explore the biological significance of this site, different modifications have been done (Table 3). Kasemsuk et al. (2013) have explained the protocol to synthesize 12-amino-andrographolide analogues via tandem aza-conjugate addition–elimination reaction of andrographolide molecule with various aniline nucleophiles. Interestingly, addition of aniline derivatives to andrographolide molecule resulted in the enhanced cytotoxic activity of the native parent compound. Further, the cytotoxicity of the amino-analogues were found to be affected by the nature of mono-substituent at the C-4 of aniline moiety as well as the presence of

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halogen atom on the aniline moiety. Their observation found 3,4-dimethoxyphenylamino derivative to be the most active, exhibiting threefolds more potency against the murine leukemia (P-388) cell line and rat glioma (ASK) cell line than ellipticine which is an established anticancer agent. Hazra et al. (2013), generated dispiro compounds, containing oxindole and pyrrolidine/pyrrolizidine rings attached to andrographolide by 1,3-dipolar cycloaddition of azomethine ylides. N-Benzyl glycine derivatives were reported to have promising biological activity (Table 3). Modifications at a-alkylidene c-butyrolactone moiety By selective oxidative degradation at a-alkylidene cbutyrolactone moiety of andrographolide side chain Nanduri et al. (2004a, b), prepared the key intermediate having aldehyde functional group. It has been utilized for synthesizing a number of structurally diverse labdane diterpenes, which have exhibited potent cytotoxic activity (Table 3). Luo et al. (2015) transformed the c-lactone ring to furan aromatic ring followed by esterification at C-3 and C-19. Derivatives having aromatic esterification at C-19 were reported to have enhanced activity.

Conclusions Among the treasure of active secondary metabolites, andrographolide stands as a promising entity. However, low solubility of the component in water as well as lipid is making it difficult to prepare direct formulations for clinical use. Keeping an eye on the indelible pharmacological properties of andrographolide, there is inevitable need to develop the bio-betters of the compound so as to overcome the limitations hurdling the path of the compound towards successful anticancer drug. Studies revealed that plausible active pharmacophores in the principle molecule include a-alkylidene c-butyrolactone ring, the conjugated double bond, C-14 hydroxyl or its ester moiety and C8-C17 double bond or epoxy moiety. Therefore, modifications in the key molecule along these moieties might result into desirable molecule/s with improved biological activity.

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Acknowledgments The authors would like to acknowledge Director, School of Biotechnology and Co-ordinator, Bioinformatics Centre, School of Biotechnology, University of Jammu for facilities. VS would like to thank Department of Science and Technology, Government of India for funding under WOS-A Project [SR/WOS-A/CS-111/2013 (G)]. Dr. Parthasarthi Das and Dr. Debaraj Mukherjee from Indian Institute of Integrative Medicine, C.S.I.R. Jammu, are also acknowledged for their helpful guidance.

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