Chemistry of withaferin-A: chemo, regio, and stereoselective synthesis of novel spiro-pyrrolizidino-oxindole adducts of withaferin-A via one-pot three-component [3+2] azomethine ylide cycloaddition and their cytotoxicity evaluation

• Published in: Molecular diversity Vol. 19; no. 2; pp. 251 - 261
• Main Authors: Bharitkar, Yogesh P., Kanhar, Satish, Suneel, Neradibilli, Mondal, Susanta Kumar, Hazra, Abhijit, Mondal, Nirup B.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.05.2015; Springer Nature B.V
• Subjects: Animals; Biochemistry; Biology; Biomedical and Life Sciences; Cell Line; Cell Survival - drug effects; Chemistry; Cycloaddition Reaction; Cytotoxicity; Full-Length Paper; Humans; Indoles; Life Sciences; Molecular Conformation; Molecular Structure; Organic Chemistry; Pharmacy; Polymer Sciences; Spiro Compounds; Stereoisomerism; Withanolides - chemical synthesis; Withanolides - chemistry; Withanolides - toxicity; X-ray crystallography; Azomethine ylide cycloaddition; Withaferin-A; Spiro-pyrrolizidino oxindole/acenaphthoquinone; 1D/2D NMR
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-015-9574-6

Withaferin-A (WA) has attracted the attention of chemists as well as biologists due to its interesting structure and various bio-activities. In light of the promising biological importance of WA as well as pyrrolidine-2-spiro-3 ′ -oxindole ring system, we became interested in the synthesis of a combined motif involving both the ring systems via the 1,3-dipolar cycloaddition of WA at Δ 2 -bond of the α , β -unsaturated carbonyl system. We now report a facile, atom-economic synthesis of novel spiro-pyrrolizidino-oxindole adducts of withaferin-A (10 compounds) via the intermolecular cycloaddition of azomethine ylides generated in situ from proline and isatins/acenaphthoquinone. The reaction is highly chemo, regio, and stereoselective affording the cis-fused products with β -orienting hydrogen. The structures were determined by 1D/2D NMR spectroscopic data analysis and unequivocally confirmed by X-ray crystallographic analysis in some cases. Bioevaluation of the compounds against six cancer lines (e.g., CHO, HepG2, HeLa, HEK 293, MDCK-II, and Caco-2) identified 4 promising potential anticancer compounds. Graphical Abstract