Design, synthesis and biological evaluation of novel small molecule inhibitors for early diagnosis and therapy of diseased states

Abstract

Cancer is the second leading cause of death globally after cardiovascular disease. In 2019, according to the National Centre for Health Statistics report, 606,880 cancer deaths are projected to occur in the United States of America. Over the years, the burden of cancer incidence has shifted to low and middle-income countries especially to India because of relatively low cancer awareness, inadequacy in the availability of early diagnostic tools and lack of affordable curative services compared to patients in high income-countries. Among all the cancers, prostate cancer (PCa) is the second most diagnosed cancer in men in Western countries. A recent report reveals that approximately 174,650 new PCa cases were registered and 31,620 estimated deaths took place in the year 2019 in the Western countries. The epidemiology of PCa in India as per Population Based Cancer Registries (PBCRs) reveal that the incidence of PCa is high inmetropolitan cities like Delhi, Kolkata, Pune, etc. The cumulative cost to treat PCa is very high and advanced stages of PCa drastically affect the quality of life due to bone disintegration, pain, obstruction of urination, and erectile dysfunction along with other health issues. The treatment of advanced stages of PCa is difficult because of metastasis to distant organs. Therefore, early detection of the disease plays a pivotal role to constitute an effective treatment strategy for lowering mortality. Recently, the development of targeted diagnostic and therapeutic tools for a lethal disease like cancer has gained significant attention in the field of medicinal chemistry research. Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), or N-acetyl-aspartyl-glutamate peptidase I (NAAG peptidase), is a useful biomarker for imaging and therapy of PCa. PSMA is an integral binuclear zinc peptidase transmembrane protein predominantly expressed in the epithelial cells of the malignant prostate gland. The biomarker belongs to a family of cell surface transmembrane proteins over-expressed during prostate carcinoma and exploited to deliver chemical tools for the early diagnosis of prostatemalignancy. PSMA also found to be expressed in the neovasculature of solid tumors in brain, bladder, and breast, etc., PSMA undergoes internalization or endocytosis, after binding with inhibitors or ligands and targeted bioconjugates, through clathrin-coated pits and quickly recycles to the cell surface to repeat the rounds of internalization. Collectively, these unique qualities make PSMA an interesting as well as an excellent candidate for applications in bioimaging and tumortargeted drug delivery. Various efforts have been made to design and synthesize low molecular weight inhibitors or ligands for targeting PSMA.The main objective of the thesis work is to design and synthesize new small molecular weight ligands and subsequently transform them to potential diagnostic and therapeutic bioconstructs for early diagnosis and treatment of PSMA+ cancers. The thesis work comprises of following chapters: 1. Aminoacetamides: A new class of small molecule inhibitors or ligands for prostate specific membrane antigen expressing (PSMA+) cancers 2. Synthesis of fluorescent and radiopharmaceutical bioconjugates using aminoacetamide as targeting ligand for detection of prostate specific membrane antigen expressing (PSMA+) cancers3. Design, synthesis and biological evaluation of novel thiourea derivatives as small molecule inhibitors for prostate specific membrane antigen 4. Tyrosine-based asymmetric urea ligand for prostate carcinoma: Tuning biological efficacy through in silico studies 5. Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labeled chelating peptide conjugates as a theranostic tool for cancer