The 2-carboxamide derivatives of estrone (E1) and estradiol (E2) offer untapped anticancer potential, mimicking active 2-methoxyestradiol (2ME2). We synthesized a 12-member library via a mesyl chloride (MsCl)-mediated protocol that overcame steric hindrances plaguing conventional couplings. Amidation of 3-OAc-protected 2-carboxyestrone (2-1CE) using standard activating agents (DCC, CDI and ethyl chloroformate) failed or gave low conversions/complex mixtures, which we attribute to steric congestion around the reaction centre, including the C-2 substituent and the incoming amine partner. In contrast, MsCl activation under basic conditions delivered morpholine, pyrrolidine, pyrimidine, diethyl-, cyclopropyl-, and bis(methoxyethyl)amides in 61–92% yields after purification. Stereoselective reduction afforded E2 analogues, fully characterized by NMR/HRMS. Bioscreening against A549, DU-145, HeLa, MCF-7 (cancerous) and MRC-5 (non-cancerous) cells demonstrated cancer selective cytotoxicity of cyclopropylamides (IC₅₀ 11.4–16.7 μM), with p53/p21/Bax/caspase-3-mediated apoptosis confirmed by gene profiling. This work underscores the superior activation potential of MsCl for 2-carboxyestrogen amidation and positions cyclopropyl-2-carboxamides as high-potential leads for next-generation steroid chemotherapeutics and mechanistic studies. • 2-carboxyestrone via regioselective Friedel-Crafts acylation/haloform reaction. • MsCl-mediated C-2 amidation with different amines enabled. • Route to structurally diverse C-2-carboxamides for bioevaluation. • Cyclopropyl carboxamides show cancer-selective potency. • SAR favors primary amine-derived C-2 carboxamides.
Novak et al. (Sun,) studied this question.