Synthesis and Cytotoxicity Evaluation of C4‐ and C5‐Modified Analogues of the α,β‐Unsaturated Lactone of Pironetin

Abstract

Pironetin is a natural product with potent antiproliferative activity that forms a covalent adduct with α‐tubulin via conjugate addition into the natural product's α,β‐unsaturated lactone. Although pironetin's α,β‐unsaturated lactone is involved in its binding to tubulin, the structure–activity relationship at different positions of the lactone have not been thoroughly evaluated. For a systematic evaluation of the structure–activity relationships at the C4 and C5 positions of the α,β‐unsaturated lactone of pironetin, twelve analogues of the natural product were prepared by total synthesis. Modifying the stereochemistry at the C4 and/or C5 positions of the α,β‐unsaturated lactone of pironetin resulted in loss of antiproliferative activity in OVCAR5 ovarian cancer cells. While changing the C4 ethyl substituent with groups such as methyl, propyl, cyclopropyl, and isobutyl were tolerated, groups with larger steric properties such as an isopropyl and benzyl groups were not.

TiCl4‐Promoted Asymmetric Aldol Reaction of Oxazolidinones and its Sulphur‐Congeners for Natural Product Synthesis

“…The aldehyde 100.2 , from 100.1 introduced several groups at the C4 position via the syn ‐aldol reaction of the titanium enolate of thiazolinethiones 70.2, 86.3 and 100.3 yielding the intermediates 100.4 (Scheme 100). [111] …”

Molecular Docking of Cryptoconcatones to α-Tubulin and Related Pironetin Analogues

“…The unique capacity of PRN to interfere with microtubule assembly via α-tubulin binding, coupled with its antitumor properties, have stimulated the search for more potent analogues. Over the past 20 years, synthetic approaches have been explored to produce PRN via different chemical routes [ 18 , 19 , 20 , 21 , 22 ] and to generate simplified PRN derivatives with improved pharmacological properties and metabolic stability [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Hybrid molecules combining the scaffold of PRN with other MTAs, such as combretastatin and colchicine, have been designed as well [ 30 , 31 , 32 ].…”

Identification of the Metabolic Profile of the α-Tubulin-Binding Natural Product (−)–Pironetin

“…Pironetin is the only natural product structurally characterized by X-ray crystallography to bind α-tubulin. Pironetin covalently binds to Cys316 of α-tubulin (Figure B). , Due to pironetin’s interesting properties, several groups have recently reported the synthesis and in vitro evaluation of pironetin analogs, both simplified − and fully elucidated. , While pironetin has promising in vitro activity, the causes of the poor in vivo activity need to be identified and addressed in order to arrive at a lead compound. To address these goals, we report the identification of pironetin’s major metabolites in human liver microsomes using mass spectrometry and semisynthesis.…”