ABSTRACT
Simple and efficient method was established for the synthesis of a new family of 14α-O-(andrographolide-3-subsitutedisoxazole-5-carboxylate) derivatives (10a-j) from naturally occurring andrographolide (1) by selective esterification with propiolic acid at C-14 using protection and deprotection strategy followed by metal free 1,3-dipolar cycloaddition with aryl nitrile oxides. All the synthesised derivatives were tested for their cytotoxicity against HCT-15, HeLa and DU145 cell lines. Most of the compounds exhibited improved cytotoxic activity compared to the parent molecule andrographolide (1), as the compounds 10b, 10c, 10i, 10j, 11d and 11f showed significant cytotoxicity against three cancer cell lines. Except the compound 10b and 11d, all the compounds did not inhibit the normal cell line (VERO). Based on these studies isoxazole ester derivatives at C-14 of andrographolide with various substitutions promoting anticancer activities and better safety profiles. Further studies in this direction with improved water solubility and oral bioavailability are in progress in future.
Subject(s)
Antineoplastic Agents , Diterpenes , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation , Diterpenes/pharmacology , Drug Screening Assays, Antitumor , Humans , Structure-Activity RelationshipABSTRACT
A series of novel 14α-O-(1,4-disubstituted-1,2,3-triazolyl) ester derivatives of andrographolide (5a-n) were synthesized from andrographolide (1). For this endeavour, selective esterification at C-14 hydroxyl group of andrographolide (1) with propiolic acid via protection, deprotection strategy followed by 1,4-regioselective [1,3]dipolar cycloaddition of alkyne, azide using Cu(I) catalyzed Click chemistry. All the synthesized derivatives were screened for their cytotoxicity on HCT-15, HeLa and K562 cell lines. Compounds 5c and 5j showed highest activity against HCT-15 and K562 cell lines whereas compound 5a displayed activity in all the three cell lines. Loss of cell viability was not observed with the non-transformed cell line MRC-5 with compounds 5j, 5k, 5h and 2 indicating cytotoxic activity of these compounds towards cancer cell lines. Further, molecular docking analysis and SAR studies of highly active compounds 5c and 5j revealed enhanced binding affinity to the target NF-κB protein.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Diterpenes/chemistry , Alkynes/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Survival/drug effects , Click Chemistry , Cycloaddition Reaction , Diterpenes/chemical synthesis , Esters/chemistry , HeLa Cells , Humans , Molecular Docking Simulation , NF-kappa B/chemistry , NF-kappa B/metabolism , Propionates/chemistry , Structure-Activity RelationshipABSTRACT
A series of new benzofuran/oxadiazole hybrids (8a-n) was synthesized from 2H-chromene-3-carbonitriles (3a-c) through the multistep synthetic methodology, and these hybrids are known to exhibit anticancer activities. All the compounds were evaluated for their in vitro cytotoxicity against the HCT116 and MIA PaCa2 cell lines. Compounds 6a (IC50 : 9.71 ± 1.9 µM), 6b (IC50 : 7.48 ± 0.6 µM), and 6c (IC50 : 3.27 ± 1.1 µM) displayed a significant cytotoxic activity, whereas compounds 8d and 8e exhibited good activity against both cell lines. The depletion of glycogen synthase kinase-3ß (GSK3ß) induces apoptosis through the inhibition of basal NF-κB activity in HCT116 colon cancer cells and MIA PaCa2 pancreatic cancer cells. Molecular docking of compounds 6a, 6b, 6c, 8d, and 8e with GSK3ß demonstrated the best binding affinity, correlating with the biological activity assay. Furthermore, the structure-activity relationship of these novel compounds reveals promising features for their use in anticancer therapy.
