Synthesis and anticancer evaluation of tryptanthrin appended spiro1-nitropyrrolizidine derivatives by the three-component reaction of tryptanthrin, l-proline and β-nitrostyrene

Abstract

Tryptanthrin incorporated 1-nitropyrrolizidines were synthesized with high regiospecificity in diastereomerically pure forms by the one-pot three component reaction of tryptanthrin, l-proline and β-nitrostyrene. The cis-relationship between the protons in carbons 1, 2 and 8 of the products 4a-p was confirmed by 1D NOE analysis and further support for the cis-cycloadduct formation, through endo attack of S-shaped ylide, was gained computationally. In silico docking studies, revealed that compounds 4j and 4k were the best candidates for anticancer screening and further in vitro analysis of these compounds against human breast cancer cell line-MCF-7 indicated mild activity with IC₅₀ values 41.57 ± 0.41 µg/mL and 65.94 ± 0.34 µg/mL respectively. Results from ADMET-AI web server indicated the higher bioavailability value with a good BBB (Blood Brain Barrier) penetration score of 0.80 and 0.77 for 4j and 4k respectively. Also, both the compounds exhibited good human intestinal absorption (HIA) value, less carcinogenicity (0.41 and 0.42) and high excretion rate (91.55 % and 89.96 %).