Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization

Bioorganic & Medicinal Chemistry
Christine A HerdmanKevin G Pinney

Abstract

The discovery of 3-methoxy-9-(30,40,50-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its potent biological activity as an inhibitor of tubulin polymerization and its cytotoxicity (in vitro) against human cancer cell lines, has resulted in studies focused on new analogue design and synthesis. Our goal was to probe the relationship of structure to function in this class of anticancer agents. A series of twenty-two new benzosuberene-based analogues of KGP18 was designed and synthesized. These compounds vary in their methoxylation pattern and separately incorporate trifluoromethyl groups around the pendant aryl ring for the evaluation of the effect of functional group modifications on the fused six-membered aromatic ring. In addition, the 8,9-saturated congener of KGP18 has been synthesized to assess the necessity of unsaturation at the carbon atom bearing the pendant aryl ring. Six of the molecules from this benzosuberene-series of compounds were active (IC50 < 5 lM) as inhibitors of tubulin polymerizati...Continue Reading

References

Jun 5, 1991·Journal of the National Cancer Institute·A MonksA Vaigro-Wolff
Jan 1, 1990·Cancer Chemotherapy and Pharmacology·A T McGown, B W Fox
Jul 1, 1981·Biochimica Et Biophysica Acta·E Hamel, C M Lin
May 12, 1995·Journal of Medicinal Chemistry·G R PettitF Hogan
May 18, 1999·Bioorganic & Medicinal Chemistry Letters·K G PinneyE Hamel
Jun 7, 2002·Acta Crystallographica. Section C, Crystal Structure Communications·Mallinath B HadimaniKevin G Pinney
Feb 24, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ian G KirwanMike C Bibby
Jun 16, 2004·Cancer·Dietmar W SiemannMichael R Horsman
Feb 19, 2005·Current Oncology Reports·Matthew M CooneyScot C Remick
Jun 2, 2005·Nature Reviews. Cancer·Gillian M TozerBruce C Baguley
Apr 5, 2007·Nature Protocols·Vanicha Vichai, Kanyawim Kirtikara
Nov 22, 2007·Expert Opinion on Therapeutic Targets·Chryso Kanthou, Gillian M Tozer
Feb 12, 2008·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Dawen ZhaoRalph P Mason
Feb 16, 2011·Integrative Biology : Quantitative Biosciences From Nano to Macro·Ralph P MasonKevin G Pinney
Nov 5, 2013·Bioorganic & Medicinal Chemistry·Rajendra P TanpureKevin G Pinney
Nov 12, 2013·Bioorganic & Medicinal Chemistry Letters·Zecheng ChenFrank Loganzo

❮ Previous
Next ❯

Citations

Oct 11, 2017·Expert Opinion on Therapeutic Patents·Haider BehbehaniThoraya A Farghaly
Jun 19, 2019·Current Topics in Medicinal Chemistry·Yongtao DuanChuanjun Song
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Li LiuRalph P Mason
Dec 4, 2020·Journal of the American Chemical Society·Roshan K DhunganaRamesh Giri

❮ 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.