Discovery of indolizine lactones as anticancer agents and their optimization through late-stage functionalization

Abstract

Indolizines fused with a seven-member lactone ring were identified as a promising scaffold in the search for new anticancer agents. Through a modular synthetic sequence, a library of cis and trans indolizines lactones had their antiproliferative activity evaluated against hormone-refractory prostate DU-145 and triple-negative breast MDA-MB-231 cancer cell lines. A methoxylated analogue was identified as an initial hit against MDA-MB-231 and late-stage functionalization of the indolizine core led to analogues within potencies up to twenty times higher than the parent precursor.

Scheme 1. Examples of indolizine motifs founded in compounds with anticancer activity and common strategies for their synthesis.

Scheme 2. Reported asymmetric synthesis of an indolizine lactone (Coelho and List, 2017) and the molecular sites available for further modifications during the investigation of biological activities of 4.

Fig. 1. Structural features of indolizines lactones founded in compounds with anticancer proprieties.

Scheme 3. Synthetic sequence to both diastereoisomers of indolizines lactones. ^aThe relative configurations of 5 were determined after the lactonization step.

Scheme 4. One-pot synthesis of 5f hydroxy esters.

Scheme 5. Synthesis of lactams 7 and partial hydrogenation of cis-4f. Condition A: NEt₃ (0.022 M) reflux, overnight B: toluene (0.025 M), NEt₃ (12 equiv.) reflux, overnight.

Scheme 6. Synthesis of lactams 7 and partial hydrogenation of cis-4f.

Scheme 7. Late-stage functionalization of cis-4f: (i) PhSH (2 equiv.), KI (10%), TBHP (2 equiv.), DMSO (0.1 M), 60 °C, 22 h. (ii) TFFA (1.25 equiv.), NEt₃ (1.5 equiv.), DCM (0.02 M), 0 °C, 1 h. (iii) n-butyl acrylate (4 equiv.), [Cp*RhCl₂]₂ (4 mol%), AgSbF₆ (0.16 equiv.), Cu(OAc)₂. H₂O (2.1 equiv.), DCE (0.1 M), 100 °C.

Fig. 2. IC₅₀ values (μM) of cis-4f analogues. Selectivity index values (SI = CC₅₀/IC₅₀) between cancer cell lines (DU-154 and MDA-MB-231) and systemic (FC3H and HFF-1) and local non-tumour cells [RWPE-1 (prostate) and MCF-10A (breast)] are listed in parentheses. ND: not determined.