Synthesis and cytotoxicity of novel 14α-O-(andrographolide-3-subsitutedisoxazole-5-carboxylate) derivatives.

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.

Synthesis and cytotoxicity of novel 14α-O-(1,4-disubstituted-1,2,3-triazolyl) ester derivatives of andrographolide.

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.