Synthesis of novel beta-lactone inhibitors of fatty acid synthase.

Journal of Medicinal Chemistry
Robyn D RichardsonJeffrey W Smith

Abstract

Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the alpha- and beta-alkyl chains, their chemical composition, and amino ester substitutions were altered and the resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display an increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.

References

Dec 1, 1980·The Journal of Antibiotics·H UmezawaS Takahashi
Apr 1, 1994·Experimental Cell Research·R BertrandY Pommier
Feb 22, 2002·International Journal of Cancer. Journal International Du Cancer·Johannes V SwinnenGuido Verhoeven
Mar 18, 2004·Cancer Research·Steven J KridelJeffrey W Smith
May 13, 2004·The Journal of Biological Chemistry·Lynn M KnowlesJeffrey W Smith
Oct 28, 2004·Proceedings of the National Academy of Sciences of the United States of America·Bornali ChakravartyFlorante A Quiocho
Feb 25, 2005·Lipids·Subrahmanyam S Chirala, Salih J Wakil
Oct 14, 2005·Journal of the American Chemical Society·Arnab K ChatterjeeRobert H Grubbs
Jul 10, 2007·Nature Structural & Molecular Biology·Charles W PembleW Todd Lowther
Jul 11, 2007·Molecular Cancer Therapeutics·Robyn D Richardson, Jeffrey W Smith
Sep 21, 2007·Nature Reviews. Cancer·Javier A Menendez, Ruth Lupu
Nov 1, 2007·Expert Opinion on Investigational Drugs·Steven J KridelCharles W Pemble

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Citations

Jul 6, 2011·Journal of Medicinal Chemistry·Hanley N Abramson
Mar 4, 2010·Organic Letters·Phanindra K M VenukadasulaPaul R Hanson
Jun 26, 2010·Chemical Communications : Chem Comm·Mun H NgaiMartin J Lear
Mar 26, 2009·Journal of the National Cancer Institute·Toshiro MigitaMassimo Loda
Apr 9, 2010·Future Oncology·Richard FlavinMassimo Loda
May 12, 2010·Current Opinion in Chemical Biology·Arthur F Kluge, Russell C Petter
Mar 18, 2008·Bioorganic & Medicinal Chemistry Letters·Wei ZhangDaniel Romo
Dec 3, 2010·The Journal of Pathology·Richard FlavinMassimo Loda
Oct 6, 2016·Expert Opinion on Drug Discovery·Thelma S Angeles, Robert L Hudkins
Oct 14, 2014·ACS Catalysis·Valerie E FakoJing-Yuan Liu
Sep 19, 2017·Expert Opinion on Therapeutic Targets·Javier A Menendez, Ruth Lupu
Feb 5, 2016·Journal of Cellular Physiology·William B KinlawNancy B Kuemmerle
Feb 23, 2012·Organic & Biomolecular Chemistry·Sylvain AubryDavid Crich
Sep 6, 2011·Organic & Biomolecular Chemistry·Sylvain AubryDavid Crich
Mar 16, 2018·ACS Medicinal Chemistry Letters·Xiaofan LiuGeorge A O'Doherty

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