Ponatinib: A comprehensive drug profile.

Ponatinib is a prescription medication used to treat a rare form of blood cancer called Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) that is resistant to other treatments. It belongs to a class of drugs called tyrosine kinase inhibitors, which work by blocking abnormal proteins that promote the growth of cancer cells. In this chapter, the synthesis methods and physicochemical properties of ponatinib were reviewed, besides the characterization of the ponatinib structure using different techniques such as elemental analysis, IR, UV, (1H and 13C) NMR, MS, and XRD. Furthermore, the compendial method for analysis of ponatinib was not found, while the literature review of a non-compendial method for analysis of ponatinib, such as spectroscopic, chromatographic, and immunoassay methods, was covered. Moreover, pharmacology and biochemistry were surveyed in the pharmacokinetic and pharmacodynamic studies.

Avanafil: A comprehensive drug profile.

Avanafil is an oral medication used to treat erectile dysfunction (ED). As a phosphodiesterase type 5 (PDE5) inhibitor, it functions by inhibiting the PDE5 enzyme, which ultimately results in increased levels of cyclic guanosine monophosphate (cGMP) and improved blood flow to the penis. Approved by the FDA in 2012, avanafil is recognised for its rapid onset of action, short half-life, and favourable side-effects profile. While it has been explored for other potential therapeutic applications, its current approved use is limited to ED and should be used as prescribed by a medical professional. This chapter provides a comprehensive review of avanafil, encompassing its nomenclature, physicochemical properties, methods of preparation, and identification. Various techniques for analysing avanafil, such as electrochemical analysis, spectrophotometric, spectrofluorimetric, and chromatographic techniques, are discussed. The pharmacology of avanafil, including its pharmacokinetics and pharmacodynamics, is also examined.

Synthesis, enzyme inhibition assay, and molecular modeling study of novel pyrazolines linked to 4-methylsulfonylphenyl scaffold: antitumor activity and cell cycle analysis.

Antitumor activity using 59 cancer cell lines and enzyme inhibitory activity of a newly synthesized pyrazoline-linked 4-methylsulfonylphenyl scaffold (compounds 18a-q) were measured and compared with those of standard drugs. Pyrazolines 18b, 18c, 18f, 18g, 18h, and 18n possessed significant antitumor activity, with a positive cytotoxic effect (PCE) of 22/59, 21/59, 21/59, 48/59, 51/59, and 20/59, respectively. The cancer cell lines HL60, MCF-7, and MDA-MB-231 were used to measure the IC50 values of derivatives 18c, 18g, and 18hvia the MTT assay method, and the results were compared with those of reference drugs. Derivatives 18g and 18h showed potent and broad-spectrum antitumor activities against HL60 (IC50 of 10.43, 8.99 µM, respectively), MCF-7 (IC50 of 11.7 and 12.4 µM, respectively), and MDA-MB-231 (IC50 of 4.07 and 7.18 µM, respectively). Compound 18c exhibited strong antitumor activity against HL60 and MDA-MB-231 cell lines with IC50 values of 8.43 and 12.54 µM, respectively, and moderate antitumor activity against MCF-7 cell lines with an IC50 value of 16.20 µM. Compounds 18c, 18g, and 18h remarkably inhibited VEGFR2 kinase (IC50 = 0.218, 0.168, and 0.135 µM, respectively) compared with the reference drug sorafenib (IC50 = 0.041 µM). Compounds 18g and 18h effectively inhibited HER2 kinase (IC50 = 0.496 and 0.253 µM, respectively) compared with erlotinib (IC50 = 0.085 µM). Compound 18h inhibited EGFR kinase (IC50 = 0.574 µM) with a potency comparable with that of the reference drug erlotinib (IC50 = 0.105 µM). Pyrazolines 18c, 18f, and 18h arrested the S/G2 phase of the cell cycle in HL-60 cells. In addition, derivatives 18c, 18f, and 18h revealed lower Bcl-2 protein expression anti-apoptotic levels and higher Bax, caspase-3, and caspase-9 expression levels. Molecular docking studies of derivative 18h into the binding sites of EGFR, HER2, and VEGFR2 kinases explored the interaction mode of these pyrazoline derivatives and their structural requirements for antitumor activity.

S-Alkylated quinazolin-4(3H)-ones as dual EGFR/VEGFR-2 kinases inhibitors: design, synthesis, anticancer evaluation and docking study.

Dual targeting by a single molecule has emerged as a promising strategy for fighting cancer. In this study, a new set of 2-thioquinazolin-4(3H)-ones as potential anti-cancer surrogates endowed with dual EGFR/VEGFR-2 kinases inhibitory activities were synthesized. The anti-tumor potency of the newly synthesized candidates 4-27 was evaluated against a panel of four cancer cell lines. The prepared candidates 4-27 showed comparable activity to that of the standard drug sorafenib. For instance, compound 4 (IC50 = 1.50-5.86 µM) and compound 20 (IC50 = 4.42-6.39 µM) displayed superior potencies against all cell lines compared to sorafenib (IC50 = 5.47-7.26 µM). Dual EGFR/VEGFR-2 inhibitory activities of the most active analogues (4, 11, and 20) were investigated. Compound 4 showed comparable EGFR/VEGFR-2 inhibitory activity to the used control drugs. Flow cytometric analysis indicates that the most potent analogue 4 stopped the cell cycle at the G1 phase and induced 46.53% total apoptosis in HCT-116 cells that was much more powerful than the untreated cells with 2.15% apoptosis. Molecular docking and dynamic simulations of 4, 11, and 20 with EGFR and VEGFR-2 were performed to examine the binding mode and interaction within the enzyme binding pockets.