Synthesis of Novel 2,3,4-trisubstituted-oxazolidine Derivatives and In Vitro Cytotoxic Evaluation

Abstract

We have previously reported the discovery of cytotoxic and pro-apoptotic hit compound 1,1-dimethylethyl (S)- 2,2-dimethyl-4-[(3-nitrophenoxy)methyl]-3-oxazolidinecarboxylate 1 against leukemia cells. In the present work we describe the synthesis of 25 derivatives of this hit varying the substituent at ring or stereochemistry of the oxazolidine ring and evaluated them against human cancer cells lines. Six compounds exerted significant activity against HL60 promyelocytic leukemia cells with IC50 in low micromolar range (4-18 μM) and three compounds displayed activity against MDA-MB231 breast cancer cells (25-37 μM). In vitro cytotoxicity on normal cells PBMC (human peripheral blood mononuclear cells) was also evaluated. Compounds 7e (p-NO2, S) and 7m (p-COOCH3, S) showed good antiproliferative activity against HL60 (4 and 5 μM) and MDA-MB231 (37 and 25 μM) without affecting lymphocyte proliferation in PBMC, indicating low toxicity to normal cells. Besides, compound 7e induced DNA fragmentation on about 100% of HL60 cells at 50 μM. In this case, it was more potent than 7m and lead 1. This indicated that compound 7e has a great pro-apoptotic potential.

Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors

“…To synthesize compounds 1i , 1j , 1m , 1p , and 1q , the amines coupled to position 2 were previously prepared in two steps. First, we coupled an aniline or a morpholine to p -nitrobenzoic acid 6 , and after that the nitro group was reduced to amino in the presence of aqueous hydrazine giving 8a or 8b (Scheme ).…”

“…Purine analogs were prepared starting from 2,6-dichloro-9 H -purine 12 , which was methylated with iodomethane . The resulting 2,6-dichloro-9-methyl-9 H -purine 13 was treated under similar, previously described conditions with benzylamine providing intermediate 14 .…”