Synthesis and structure–activity relationships of andrographolide analogues as novel cytotoxic agents

Nanduri, Srinivas; Nyavanandi, Vijay Kumar; Thunuguntla, Siva Sanjeeva Rao; Kasu, Sridevi; Pallerla, Mahesh K.; Ram, Phulgan; Rajagopal, Sriram; Kumar, Rakesh; Rajagopalan, Rukkumani; Babu, J. Moses; Vyas, K.; Devi, A. Sivalakshmi; Reddy, G. Om; Venkateswarlu, A.

doi:10.1016/j.bmcl.2004.06.090

Cited by 157 publications

(56 citation statements)

References 16 publications

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“…S2B), suggesting that the ␣,␤-unsaturated ␥-lactones and the covalent protein binding of Andro are critical to its anti-cancer property. Previous structure-activity relationship studies suggested that the ester derivative of Andro at the C14 hydroxyl group did not affect the C12-C13 moiety or the drug's potency (35)(36)(37). Therefore, we introduced an alkyne handle using the ester linkage at the C14 position to synthesize the clickable probe P1 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

Wang

Tan

Nguyễn

et al. 2014

Molecular & Cellular Proteomics

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Drug target identification is a critical step toward understanding the mechanism of action of a drug, which can help one improve the drug's current therapeutic regime and expand the drug's therapeutic potential. However, current in vitro affinity-chromatography-based and in vivo activity-based protein profiling approaches generally face difficulties in discriminating specific drug targets from nonspecific ones. Here we describe a novel approach combining isobaric tags for relative and absolute quantitation with clickable activity-based protein profiling to specifically and comprehensively identify the protein targets of andrographolide (Andro), a natural product with known anti-inflammation and anti-cancer effects, in live cancer cells. We identified a spectrum of specific targets of Andro, which furthered our understanding of the mechanism of action of the drug. Our findings, validated through cell migration and invasion assays, showed that Andro has a potential novel application as a tumor metastasis inhibitor. Moreover, we have unveiled the target binding mechanism of Andro with a combination of drug analog synthesis, protein engineering, and mass-spectrometry-based approaches and determined the drugbinding sites of two protein targets, NF-B and actin. Molecular & Cellular Proteomics 13: 10.1074/mcp. M113.029793, 876-886, 2014.As most drugs exert pharmacological effects by interacting with their target proteins, the identification of these target proteins is a critical step in unraveling the mechanisms of drug action. It is also imperative for our understanding of the pharmacodynamics of a known drug, suggesting potentially unrevealed actions and thus refining future clinical applications of the substance. Traditional approaches used to identify protein targets of a drug typically utilize immobilized drug affinity chromatography coupled with mass spectrometry (MS) 1 (1, 2). These methods can be applied to cell lysates, but not in an in vivo setting, because of the requirement of a solid support. In vitro target profiling might not accurately reflect the drug's actions in the in vivo physiological environment. To overcome this limitation, several groups have used activity-based protein profiling (ABPP) combined with bio-orthogonal click chemistry to identify drug targets both in vitro and in vivo (supplemental Fig. S1) (3-15). ABPP probes exert their functions via covalent reactions with the target proteins or photoaffinity-based labeling via the incorporation of photoreactive groups. With the increasing sensitivity of modern MS platforms, low-abundance protein targets can be successfully identified. Although both conventional affinity chromatography and recent ABPP-based methods allow us to detect a set of candidate protein targets for a drug, it remains difficult to 1 The abbreviations used are: MS, mass spectrometry; ABPP, activity-based protein profiling; ICABPP, clickable activity-based protein profiling; iTRAQ, isobaric tags for relative and absolute quantitation; DMSO, dimethyl sulfoxide; Andro, androgr...

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Section: Resultsmentioning

confidence: 99%

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

Wang

Tan

Nguyễn

et al. 2014

Molecular & Cellular Proteomics

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“…6) Extensive research has revealed that Andrographis paniculata has a surprisingly broad range of pharmacological effects and some of them are extremely beneficial, such as antiinflammatory, [7][8][9][10][11] antidiarrhoeal, 12,13) antiviral, 14) anti-malarial, 15,16) hepatoprotective, [17][18][19][20][21][22][23][24][25][26][27][28][29] cardiovascular, 30,31) anticancer, [32][33][34][35][36][37][38][39] and immunostimulatory [40][41][42][43][44] activities. On the other hand, male reproductive toxicity 45) and cytotoxicity 46) of this plant have been reported as well.…”

Section: Introductionmentioning

confidence: 92%

Pharmacological Aspects of Andrographis paniculata on Health and Its Major Diterpenoid Constituent Andrographolide

Jarukamjorn

Nemoto

2008

JOURNAL OF HEALTH SCIENCE

201

111

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Nowadays, research on medicinal plants has attracted a lot of attention globally. A number of evidence has been accumulated to demonstrate promising potential of medicinal plants used in various traditional, complementary, and alternative systems. In recent years, a medicinal plant, Andrographis paniculata, and its major active phytochemicals have been extensively studied for several pharmacological activities. To understand the mechanism of action, researches have to be carried out at molecular levels. The present review aims at compiling consequential compendium of pharmacological benefits of health on this plant and its major diterpenoid constituent andrographolide that have been tested in various experimental models using modern scientific methodologies.

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“…f.) Nees, named chuanxinlian in China, is one of the most important medicinal plants used in China and Southeast Asia to treat a wide spectrum of ailments, including gastric disorder, colds, influenza, and other infectious diseases [11][12][13]. Modern pharmacological studies have shown that that extracts of A. paniculata exhibit a wide range of biological activities such as antiinflammatory antiallergic, anticancer, hepatoprotective, antibacterial, immuno-stimulatory, antiviral, and other activities [14][15][16][17][18][19][20][21][22]. Number of active principles has been reported from this well-studied herb, which mainly showed a rich source of diterpene lactones, flavonoids, polyphenols, stigmasterols, and polysaccharides [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

A polysaccharide from Andrographis paniculata induces mitochondrial-mediated apoptosis in human hepatoma cell line (HepG2)

et al. 2015

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In the present study, we investigated the effects and action mechanisms of a purified polysaccharide (APWP) from Andrographis paniculata, on human hepatocellular carcinoma (HCC) HepG2 cells. The results showed that APWP was able to suppress the proliferation of HepG2 cells via inducing apoptosis. Western blot analysis revealed that dose-dependent increase in proapoptotic Bax protein and no change in antiapoptotic Bcl-2 protein in APWP-treated cells. Furthermore, exposure of tumor cells to APWP resulted in a loss of mitochondrial membrane potential (MMP) and the release of cytochrome c from the mitochondria to the cytosol. Besides, caspase-9 and caspase-3 were activated while caspase-8 was not affected in HepG2 cells followed by APWP treatment. All these results point clearly to the involvement of mitochondria-mediated signaling pathway in APWP-induced apoptosis and strongly suggest that APWP seems to be safe and effective in the prevention and treatment of HCC.

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Synthesis and structure–activity relationships of andrographolide analogues as novel cytotoxic agents

Cited by 157 publications

References 16 publications

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis

Pharmacological Aspects of Andrographis paniculata on Health and Its Major Diterpenoid Constituent Andrographolide

A polysaccharide from Andrographis paniculata induces mitochondrial-mediated apoptosis in human hepatoma cell line (HepG2)

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