Novel route to chaetomellic acid A and analogues: Serendipitous discovery of a more competent FTase inhibitor

Franco Bellesia, Seoung Ryoung Choi, Fulvia Felluga, Giuliano Fiscaletti, Franco Ghelfi*, Maria Cristina Menziani, Andrew F. Parsons, C. Dale Poulter, Fabrizio Roncaglia, Massimo Sabbatini, Domenico Spinelli

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

A new practical route to chaetomellic acid A (ACA), based on the copper catalysed radical cyclization (RC) of (Z)-3-(2,2-dichloropropanoyl)-2- pentadecylidene-1,3-thiazinane, is described. Remarkably, the process entailed: (i) a one-pot preparation of the intermediate N-α-perchloroacyl-2-(Z)- alkyliden-1,3-thiazinanes starting from N-(3-hydroxypropyl)palmitamide, (ii) a two step smooth transformation of the RC products into ACA and (iii) only one intermediate chromatographic purification step. The method offers a versatile approach to the preparation of ACA analogues, through the synthesis of an intermediate maleic anhydride with a vinylic group at the end of the aliphatic tail, a function that can be transformed through a thiol-ene coupling. Serendipitously, the disodium salt of 2-(9-(butylthio)nonyl)-3-methylmaleic acid, that we prepared as a representative sulfurated ACA analogue, was a more competent FTase inhibitor than ACA. This behaviour was analysed by a molecular docking study.

Original languageEnglish
Pages (from-to)348-358
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number1
DOIs
Publication statusPublished - 1 Jan 2013

Bibliographical note

Funding Information:
We thank the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR, PRIN 20085E2LXC-004, 20085E2LXC-003), the National Institute of Health (NIH Grant GM 21328) and the EU (under the ERASMUS scheme) for financial support.

Keywords

  • Chaetomellic acid A
  • Farnesyl pyrophosphate
  • FTase inhibitors
  • Modelling studies
  • Radical cyclization

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