Abstract
Pathological angiogenesis is a hallmark of cancer; accordingly, a number of anticancer FDA-approved drugs act by inhibiting angiogenesis via different mechanisms. However, the development process of the most potent anti-angiogenics has met various hurdles including redundancy, multiplicity, and development of compensatory mechanisms by which blood vessels are remodeled. Moreover, identification of broad-spectrum anti-angiogenesis targets is proved to be required to enhance the efficacy of the anti-angiogenesis drugs. In this perspective, a proper understanding of the structure activity relationship (SAR) of the recent anti-angiogenics is required. Various anti-angiogenic classes have been developed over the years; among them, the heterocyclic organic compounds come to the fore as the most promising, with several drugs approved by the FDA. In this review, we discuss the structure–activity relationship of some promising potent heterocyclic anti-angiogenic leads. For each lead, a molecular modelling was also carried out in order to correlate its SAR and specificity to the active site. Furthermore, an in silico pharmacokinetics study for some representative leads was presented. Summarizing, new insights for further improvement for each lead have been reviewed.
Highlights
As the second leading cause of mortality globally, cancer has become the focus for extensive research [1,2]
This process is regulated by a balance between pro- and anti-angiogenic molecules, and once that delicate balance is disturbed [11], it could lead to various diseases, especially cancer [12]
Several nitrogen-based heterocyclic drugs have been used to inhibit VEGF, for example, agents that inhibit the vascular endothelial growth factor receptors (VEGFRs) tyrosine kinase such as the pyrrolidinone-based Sunitinib were approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinibresistant gastrointestinal stromal tumor [35,36]
Summary
As the second leading cause of mortality globally, cancer has become the focus for extensive research [1,2]. Angiogenesis is essential for formation of a new vascular network to supply nutrients, oxygen, and immune cells, as well as to remove waste products [10]. This process is regulated by a balance between pro- and anti-angiogenic molecules, and once that delicate balance is disturbed [11], it could lead to various diseases, especially cancer [12]. Most of the drugs that have been developed to combat angiogenesis have heterocyclics in their backbone as a common feature
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