Study on synthesis and anticancer activity of 17beta-estradiol-phenol/aniline nitrogen mustard derivatives

As 17 β -estradiol and its derivatives have good affinity with estrogen receptors and have unique antitumor properties, O 1 -propargyl- N 4 , N 4 -bis(2-chloroethyl)-4-aminophenol and N 4 , N 4 -dipropargyl- N 1 , N 1 -bis(2-chloroethyl)-1,4-phenylenediamine were respectively combined with 17 β -estradiol through linkers of different lengths. These targeted novel nitrogen mustard 17 β -estradiol derivatives were tested antiproliferative activity using the MTT assay. The results illustrated that these compounds were less toxicity to HL-7702 (human liver cells) and SKOV-3, though all their activity potency was moderate or weak aganist the MDA-MB-231, MCF-7 and BEL-7404 cell lines. The inhibitory activity of the O 1 -propargyl- N 4 , N 4 -bis (2-chloroethyl)-4-aminophenol derivatives (compounds III-1~6 and VII-1~4 ) were obviously better than the N 4 -dipropargyl- N 1 , N 1 -bis (2-chloroethyl) -1,4-phenylenediamine derivatives (compounds IV-1~6 and VIII-1~4 ) against tested tumor cell lines. And three hybrids (compounds III-2 , III-6 , and VII-3 ) exhibited good inhibitory activity against BEL-7404 cell line (IC 50  = 13.5, 15.3 and 13.9 μM, respectively). After that, we performed KEGG pathway analysis on compound III-6 , and the results showed that III-6 mainly induced breast cancer cell apoptosis by regulating the expression of the proteins in NF-κ B pathway.