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Author
Pascual Castells, Jana
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Abstract
In the Western world the second leading cause of death is cancer. Despite advances in recent years in diagnoses and treatments, the survival rate of cancer patients remains poor. Standard cancer treatment options have been surgery, chemotherapy, radiation therapy, and endocrine therapy. These treatments have improved survival in various types of solid tumors but drug resistance has been the leading causes of mortality. On the other hand, scientific advances in recent years have improved understanding of cancer biology.
Protein tyrosine kinases (PTKs) play a very important role in human carcinogenesis and are therefore a very important field of research in medical chemistry. In other words, because these types of proteins are involved in tumor growth, several research routes have been initiated to inhibit tyrosine kinases. These areas of research focus on the development of tyrosine kinase inhibitors for cancer therapy.
The IQS Pharmaceutical Chemistry Group (GQF) has been developing pyridine [2,3-d] pyrimidine central structure tyrosine kinase inhibitors for many years. Specifically, 4-amino-6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (20) was very attractive due to its high inhibitory capacity in front of several tumor cell lines in in vitro assay. But when switching to in vivo tests, a low activity related to bioavailability was observed, probably due to a fast metabolism and elimination of the organism. In a study with rat liver microsomes and subsequent analysis by HPLC-MS, the formation of a major metabolite could be observed by hydroxylating structure 20 at some point in the aniline ring. In order to know the exact point of oxidation and thus be able to block this metabolism so quickly through a structural modification over 20, in the present work a synthetic route has been developed to obtain the two most likely metabolites, is namely molecules 18 and 19 where the hydroxyl groups are located in the aniline ring in ortho and para position.
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