Degradation of BMS-753493, a novel epothilone folate conjugate anticancer agent

Drug Development and Industrial Pharmacy
Madhushree GokhaleFrank Rinaldi


BMS-753493 is a folate-targeted candidate being developed for the treatment of cancer. As part of preformulation efforts, our aim was twofold - to understand the major degradation pathways and, study its kinetics of degradation to aid drug product development. Given the complexity of degradation, BMS-748285, the epothilone moiety of BMS-753493 was used as model compound to evaluate the major degradation pathway viz; macrolactone versus aziridine ring hydrolysis. Hydrolysis of BMS-753493 was studied in the pH range of 1.5-9.4 in 0.05 M buffers at 0.5 ionic strength and 5-40°C. Three major pathways were identified; carbonate ester hydrolysis and hydrolysis of aziridine and macrolactone rings resulting in addition products with identical masses (m/z = 794) in the pH range of 5-7.5. Similarly, two addition products, D1 and D2 (m/z = 555) were also formed on hydrolysis of BMS-748285 under neutral pH conditions. The reaction products from BMS-748285 were isolated and characterized using LC-MS and LC-SPE-NMR (1-D ¹H and 2-D HMBC, heteronuclear single quantum coherence) analyses. LC-NMR analysis indicated an intact aziridine ring and opened macrolactone ring, resulting in D1 and D2, an isomeric hydroxy acid pair resulting from an alkyl...Continue Reading


Jul 1, 1992·Journal of Pharmaceutical Sciences·J Fassberg, V J Stella
Mar 1, 1994·Journal of Biomolecular NMR·J SchleucherC Griesinger
Dec 17, 1997·International Journal of Cancer. Journal International Du Cancer·C A LadinoV S Goldmacher
Feb 26, 2000·Proceedings of the National Academy of Sciences of the United States of America·P GiannakakouT Fojo
Oct 2, 2004·Journal of Pharmaceutical Sciences·M JumaaV J Stella
Sep 2, 2005·Journal of Pharmaceutical Sciences·Andrew R Hilgenbrink, Philip S Low
Aug 4, 2006·Drug Development and Industrial Pharmacy·P J KuehlP B Myrdal
Dec 28, 2007·Accounts of Chemical Research·Fabian FeyenKarl-Heinz Altmann

❮ Previous
Next ❯


Feb 21, 2014·Nanomedicine·Bingbing WangPhilip S Low
Jul 3, 2015·Therapeutic Advances in Medical Oncology·Ignace Vergote, Christopher P Leamon
Nov 4, 2017·Future Oncology·Kathleen N MooreMichael J Birrer
Feb 24, 2015·Nature Reviews. Drug Discovery·Madduri SrinivasaraoPhilip S Low
Feb 12, 2020·Drug Metabolism Reviews·Hanlan LiuChandra Prakash
Jun 2, 2016·Oncotarget·Anthony CheungSophia N Karagiannis
Aug 16, 2017·Pharmaceuticals·Klaudia SiwowskaCristina Müller
Nov 5, 2019·Biochimica Et Biophysica Acta. Reviews on Cancer·Urvi H GalaRobert O Williams

❮ Previous
Next ❯

Related Concepts

Trending Feeds


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 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.


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.