Design, synthesis and biological evaluation of novel thiadiazoline-thiazolone hybrids as kinase inhibitors.

Masters Degree. University of KwaZulu-Natal, Durban. 2017Cancer is a leading cause of death globally, and it was responsible for 8.8 million deaths in 2015. It is predicted that there will be 22 million new cancer cases by 2030 worldwide. Approximately, 70% of deaths from cancer occur in low- and middle-income countries. Furthermore, breast cancer is the second most common cancer among South African women and is reported to affect 1 in every 26 women. The social and economic burdens associated with cancers are severe at national and international levels hence, there is an urgent need for the development of more effective cancer therapeutics. To accomplish this aspect, in this study, thiadiazole-thiazolone (TDT) hybrids were developed as dual inhibitors of cyclindependent kinase (CDK) and kinesin spindle protein (KSP), respectively. Twenty-two novel TDT hybrid compounds (8a-v) were synthesized using multistep organic synthesis and were characterized using thin layer chromatography (TLC), infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (1H and 13C NMR), and high-resolution mass spectrometry (HR-MS). All the compounds (8a-v) were screened for their potential in vitro inhibition of validated anticancer drug targets (CDK, Abl and KSP) and cancer cell lines (MCF-7 and K562). Results obtained from these evaluations suggested that the synthesized compounds were potent inhibitors of CDK and KSP thus confirming the dual mode of action. Amongst, 8h was identified as the most potent compound with an IC50 value of 3.1 µM against CDK2 enzyme and exhibited good cytotoxicity (GI50 = 6.25 µM) against the tested cancer cell lines (MCF-7 and K-562). A brief structure-activity relationship (SAR) analysis indicated that 2- chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to the inhibition of both of the anticancer drug targets (CDK and KSP). An in silico molecular docking study using the crystal structures of the target enzymes (CDK-2 and KSP) further supported the SAR and extrapolated the importance of crucial molecular interactions in influencing the enzyme inhibitory activitie

Targeting the Colchicine Binding Site on Tubulin to Overcome Multidrug Resistance and Anticancer Efficacy of Selective Survivin Inhibitors

Tubulin inhibitors are widely used as chemotherapeutic agents, and their successis attributed to their ability to target microtubule dynamics and disrupt critical cellular functions including cell signaling, motility, intracellular trafficking, and mitosis. Interference with microtubule dynamics consequently disrupts mitotic progression and ultimately leads to apoptosis, validating microtubule dynamics as an excellent target for anticancer agents. While this class of drug has proven to be effective against many cancer types, the clinical efficacy of current tubulin inhibitors is often limited by the development of multidrug resistance. The most common form of resistance to these agents arises from the overexpression of drug efflux transporters. Extensive research efforts have attempted to develop colchicine binding site inhibitors, which are reported to be significantly less susceptible to multidrug resistance and have therapeutic advantages over agents that target the taxane and vinca alkaloid site. Herein, we evaluated the anticancer activity of novel small-molecules that target the colchicine binding site, focusing on the most promising compounds from several structural scaffolds including indolyl-imidazopyridines (DJ95 and DJ101), VERU-111 analogs with a modified indole moiety (10ab and 10bb) or 3,4,5-trimethoxyphenyl moiety (13f), and heterocyclic pyrimidines (4a, 6a, 5a, and 5b). We demonstrated the cytotoxic potency of these compounds against a variety of cancer cell lines, including malignant melanomas, taxaneresistant prostate cancer cells, and drug efflux pump-overexpressing cell lines. Their mechanism of action was revealed through tubulin polymerization inhibition, disruption of microtubule networks and mitotic spindle formation, and confirmed through X-ray crystallography, which detailed their specific molecular interactions with tubulin in the colchicine binding pocket. Furthermore, these compounds exhibited hallmark characteristics of colchicine binding site agents, such as arresting cells in the G2/M phase of the cell cycle, inducing apoptosis in a concentration-dependent manner, and impeding cancer cell proliferation and migration. Finally, the compounds were efficacious in vivo against melanoma and taxane-resistant prostate cancer xenograft tumors. Several agents were evaluated for ability to prevent melanoma metastases to the lungs in experimental mouse models, and they potently inhibited the development metastatic foci. Safety assessment by pharmacological profiling demonstrated minimal interactions to physiologically important targets and pathophysiological analysis of major organs from the in vivo treatment groups did not expose apparent drug-related injury. Several of the investigated compounds also demonstrated vascular disrupting properties by targeting tumor vasculature and inhibiting capillary-like network formation of endothelial cells. Ultimately, these compounds exhibit strong anticancer efficacy, specifically target the colchicine binding site, and have great potential as cancer therapeutics, particularly for multidrug resistance phenotypes. Another target we explored for anticancer intervention was survivin. Survivin is the smallest member the inhibitor of apoptosis protein family and its overexpression in tumor cells is been positively correlated with the development of multidrug resistance and radiation resistance. Because it is differentially expressed in healthy tissues and tumors, it is an attractive therapeutic target. Using the scaffold of UC-112, which was previously identified through virtual screening, we evaluated a series of analogs designed to optimize potency and improve selectivity to survivin over other inhibitor of apoptosis proteins. We identified compound 10f, which was highly cytotoxic to melanoma and Pglycoprotein overexpressing cell lines, induced apoptotic cascades in a concentrationdependent manner, specifically downregulated survivin protein levels, and significantly inhibited tumor growth in vivo. Ultimately, these results validated our in-depth biological investigation of novel scaffolds of survivin inhibitors and verified the anticancer efficacy of 10f

Aurora Kinase Inhibitors in Head and Neck Cancer

Aurora kinases are a group of serine/threonine kinases responsible for the regulation of mitosis. In recent years, with the increase in Aurora kinase-related research, the important role of Aurora kinases in tumorigenesis has been gradually recognized. Aurora kinases have been regarded as a new target for cancer therapy, resulting in the development of Aurora kinase inhibitors. The study and application of these small-molecule inhibitors, especially in combination with chemotherapy drugs, represents a new direction in cancer treatment. This paper reviews studies on Aurora kinases from recent years, including studies of their biological function, their relationship with tumor progression, and their inhibitors

Anticancer Agents

This book is a printed edition of the Special Issue entitled “Anticancer Agents: Design, Synthesis and Evaluation” that was published in Molecules. Two review articles and thirty research papers are included in the Special Issue. Three second-generation androgen receptor antagonists that have been approved by the U.S. FDA for the treatment of prostate cancer have been reviewed. Identification of mimics of protein partners as protein-protein interaction inhibitors via virtual screening has been summarized and discussed. Anticancer agents targeting various protein targets, including IGF-1R, Src, protein kinase, aromatase, HDAC, PARP, Toll-Like receptor, c-Met, PI3Kdelta, topoisomerase II, p53, and indoleamine 2,3-dioxygenase, have been explored. The analogs of three well-known tubulin-interacting natural products, paclitaxel, zampanolide, and colchicine, have been designed, synthesized, and evaluated. Several anticancer agents representing diverse chemical scaffolds were assessed in different kinds of cancer cell models. The capability of some anticancer agents to overcome the resistance to currently available drugs was also studied. In addition to looking into the in vitro ability of the anticancer agents to inhibit cancer cell proliferation, apoptosis, and cell cycle, in vivo antitumor efficacy in animal models and DFT were also investigated in some papers