Heterocyclization of Thiophenes Derived from Estrone Followed by Cytotoxic, HTRF Kinase and Pim-1 Kinase Evaluations.

Abstract

A wide range of heterocyclic steroidal derivatives gained a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Many pharmacological drugs containing the steroid nucleus are known in the market. Our main aim of this work was to synthesise a series of heterocyclic compounds especially thiophene and thienopyridine derivatives containing the estrone nucleus. The synthesized compounds posses antitumor and kinases inhibitions. Thiophene derivatives of estrone were synthesized and used for further heterocyclization reactions through the reaction with the different reagent. Antiproliferative evaluations and c-Met kinase, Pim-1 kinase inhibitions were performed where some compounds revealed high activities. Compounds that showed high antiproliferative activity and c-Met- kinase inhibitions were tested for all compounds. The most promising compounds 3b, 5c, 6c, 8d, 8f, 13e, 13f, 18b and 20d were further investigated against tyrosine kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 6b, 13b, 16b and 16c were selected to examine their Pim-1 kinase inhibition activity where compounds 11c, 18b and 20f showed high activities. Structure-Activity Relationship (SAR) was rationalized by looking at the varying structural features of the molecules.