Chemistry, biology, and QSAR studies of substituted biaryl hydroxamates and mercaptoacetamides as HDAC inhibitors-nanomolar-potency inhibitors of pancreatic cancer cell growth

ChemMedChem
Alan P KozikowskiKi Hwan Kim

Abstract

The histone deacetylases (HDACs) are able to regulate gene expression, and inhibitors of the HDACs (HDACIs) hold promise in the treatment of cancer as well as a variety of neurodegenerative diseases. To investigate the potential for isoform selectivity in the inhibition of HDACs, we prepared a small series of 2,4'-diaminobiphenyl ligands functionalized at the para-amino group with an appendage containing either a hydroxamate or a mercaptoacetamide group and coupled to an amino acid residue at the ortho-amino group. A smaller series of substituted phenylthiazoles was also explored. Some of these newly synthesized ligands show low-nanomolar potency in HDAC inhibition assays and display micromolar to low-nanomolar IC(50) values in tests against five pancreatic cancer cell lines. The isoform selectivity of these ligands for class I HDACs (HDAC1-3 and 8) and class IIb HDACs (HDAC6 and 10) together with QSAR studies of their correlation with lipophilicity are presented. Of particular interest is the selectivity of the mercaptoacetamides for HDAC6.

References

Jul 23, 1998·Cell·K Struhl, Z Moqtaderi
May 12, 2000·Journal of Structural Biology·A P Wolffe, D Guschin
Aug 3, 2000·Journal of the National Cancer Institute·P A MarksR A Rifkind
Mar 21, 2002·Nature Reviews. Cancer·P MarksW K Kelly
Apr 3, 2003·Nature Reviews. Molecular Cell Biology·Siavash K Kurdistani, Michael Grunstein
Sep 17, 2003·The Journal of Pharmacology and Experimental Therapeutics·Erding HuMichael Jaye
Oct 8, 2003·Current Medicinal Chemistry·Michael Curtin, Keith Glaser
Aug 26, 2004·Advances in Cancer Research·Paul A MarksWilliam Kevin Kelly
Sep 14, 2004·Journal of Combinatorial Chemistry·Gilles QuéléverJean-Louis Kraus
Oct 13, 2004·Proceedings of the National Academy of Sciences of the United States of America·Alessandro VanniniStefania Di Marco
Nov 16, 2004·Biochemical and Biophysical Research Communications·K B GlaserM L Curtin
Feb 17, 2005·Bioorganic & Medicinal Chemistry Letters·Bin ChenAlan P Kozikowski
Aug 4, 2006·Journal of Medicinal Chemistry·Takayoshi SuzukiNaoki Miyata
Apr 10, 2007·International Journal of Cancer. Journal International Du Cancer·Takashi KumagaiH Phillip Koeffler
Jun 9, 2007·Bioorganic & Medicinal Chemistry Letters·Phieng SiliphaivanhThomas A Miller

❮ Previous
Next ❯

Citations

Jul 6, 2012·Journal of Chemical Information and Modeling·Laura SilvestriRino Ragno
Jul 23, 2008·Antimicrobial Agents and Chemotherapy·Geoffrey S DowAlan P Kozikowski
Sep 13, 2013·Future Medicinal Chemistry·Michel WeïwerEdward B Holson
Nov 26, 2015·ChemMedChem·Irina N GaisinaAlan P Kozikowski
Nov 17, 2010·Cancer Letters·Alexander ArltHeiner Schäfer
Jun 23, 2009·Current Opinion in Chemical Biology·Jay Hans KalinAlan Paul Kozikowski
Feb 18, 2010·Medicinal Research Reviews·Eleni Pontiki, Dimitra Hadjipavlou-Litina
Jun 26, 2012·Biochemical Pharmacology·Sabrina DallavalleFranco Zunino
May 1, 2013·Journal of Medicinal Chemistry·Jay H Kalin, Joel A Bergman
May 7, 2013·International Journal of Molecular Sciences·Joshua Haakenson, Xiaohong Zhang
Mar 30, 2018·Frontiers in Chemistry·Wenchao LuCheng Luo
Oct 10, 2020·European Journal of Medicinal Chemistry·Maurício T TavaresSida Shen
Dec 2, 2009·Journal of Chemical Information and Modeling·Gabriella OrtoreAdriano Martinelli
Mar 25, 2017·ACS Medicinal Chemistry Letters·Ahmed T NegmeldinMary Kay H Pflum

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.