New tamoxifen analogs for breast cancer therapy: synthesis, aromatase inhibition and in silico studies

A new class of tamoxifen analogues, using McMurry reaction conditions, is described. The scheme involved the conversion of ketoprofen (6) into amide derivatives 7 and 8, by coupling with N-1,N-1-substituted propan-1,3-diamine derivatives in the presence DIC and HOB. Treatment of 7 and 8 with various ketones under McMurry reaction conditions afforded the tamoxifen analogues 9-16. All the analogues were screened in vitro for their aromatase inhibitory and antiproliferative activity against MCF-7 breast cancer cells. Compounds 10, 11 and 12 showed a potent activity against MCF-7 cell lines breast cancer with IC50 values of 0.070, 0.042 and 0.077 mu M of selectivity index (SI) 3.0, 2.5 and 2.6, respectively. Further, 12 exhibited potent activity against estrogen receptor (14.7 +/- 2.4 nM), while compound 10 was the most active analogues against aromatase with IC50 of (0.070 nM). Furthermore, all new compounds were docked into human placental aromatase enzyme and estrogen receptor and showed very good correlations with experimental IC50. Therefore, we can consider these designed compounds as starting scaffold to design an efficient drug against estrogen receptor and aromatase.Communicated by Ramaswamy H. Sarma

Automated summary

A new class of tamoxifen analogues was synthesized using McMurry reaction conditions. The analogues showed potent activity against MCF-7 breast cancer cells, with compound 10 exhibiting the highest activity against aromatase. Docking studies showed that the new compounds had good correlations with experimental IC50, suggesting their potential as starting scaffolds for designing efficient drugs against estrogen receptor and aromatase.