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

TY - JOUR

T1 - Novel route to chaetomellic acid A and analogues

T2 - Serendipitous discovery of a more competent FTase inhibitor

AU - Bellesia, Franco

AU - Choi, Seoung Ryoung

AU - Felluga, Fulvia

AU - Fiscaletti, Giuliano

AU - Ghelfi, Franco

AU - Menziani, Maria Cristina

AU - Parsons, Andrew F.

AU - Poulter, C. Dale

AU - Roncaglia, Fabrizio

AU - Sabbatini, Massimo

AU - Spinelli, Domenico

N1 - 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.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

KW - Chaetomellic acid A

KW - Farnesyl pyrophosphate

KW - FTase inhibitors

KW - Modelling studies

KW - Radical cyclization

UR - http://www.scopus.com/inward/record.url?scp=84870877847&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2012.10.034

DO - 10.1016/j.bmc.2012.10.034

M3 - Article

C2 - 23182215

AN - SCOPUS:84870877847

SN - 0968-0896

VL - 21

SP - 348

EP - 358

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 1

ER -