Mini Reviews in Medicinal Chemistry - Volume 19, Issue 4, 2019

Human insulin-like growth factor (IGF) axis affects the molecular pathogenesis of hepatocellular carcinoma (HCC), especially in the abnormality of hepatic IGF-I receptor (IGF-IR) or IGF-II expression as a key molecule in hepatocarcinogenesis. However, the over-expression of hepatic IGFIR is associated with HCC progression with largely unknown mechanisms. The IGF-IR as one key molecule of the IGF signal pathway plays an important role in the hepatocyte malignant transformation. Attaching importance to IGF-IR might improve the prognostic or the therapeutic technique of HCC. This article reviews IGF-IR alteration during HCC development, and the effects of silencing IGF-IR gene by specific short hairpin RNA on the inhibition of cell proliferation in vitro or HCC xenograft growth in vivo to elucidate it as a novel molecular-targeted therapy for HCC.

Glyoxalase system is a ubiquitous system in human cells which has been examined thoroughly for its role in different disease conditions. It is composed of Glyoxalase-I (Glo-I) and Glyoxalase- II which perform an essential metabolic process inside the cell by detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic D-lactic acid. Tumor cells are well-known for their high metabolic rate which results in elevated levels of toxic metabolites. The over-expression of Glo-I in tumor cells makes this enzyme a pivotal target for anticancer drug development. Glo-I is metalloenzyme with two polypeptide chains and encompasses two active sites with an integral zinc atoms at their center. This review aims to highlight the important role of Glo-I in different pathogenic conditions, and more importantly, it provides a thorough discussion of all known human Glo-I inhibitors since its discovery, a hundred years ago, up to date. It embraces the different classes they belong to, their design and chemical structures. We believe this review will help guide the design of novel and potent human Glo-I inhibitors by providing a handy reference for interested researchers in this target.

As noteworthy members of the terpenoid family, iridoids are a group of natural compounds that have a cyclopentane ring and hemiacetal structural features. Among them, phenylpropionyl iridoids— widely present in Bignoniaceae, Rubiaceae, Scrophulariaceae, Verbenaceae, and Oleaceae— were discovered and extracted from plants mainly between the 1980s and 2000s. Because of their unique structural features and complex stereo configurations, these compounds exhibit numerous desirable biological activities such as neuroprotective, anti-inflammatory, antimicrobial, and antitumour activities; they have received increasing interest recently. This review summarises progress in research on phenylpropionyl iridoids, including their occurrence and biological activities.

Nonalcoholic fatty liver disease (NAFLD), historically considered to be the hepatic component of the metabolic syndrome, is a spectrum of fat-associated liver conditions, in the absence of secondary causes, that may progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Disease progression is closely associated with body weight or fatness, dyslipidemia, insulin resistance, oxidative stress, and inflammation. Recently, vitamin D deficiency has been linked to the pathogenesis and severity of NAFLD because of vitamin D “pleiotropic” functions, with roles in immune modulation, cell differentiation and proliferation, and regulation of inflammation. Indeed, several studies have reported an association between vitamin D and NAFLD/NASH. However, other studies have failed to find an association. Therefore, we sought to critically review the current evidence on the association between vitamin D deficiency and NAFLD/NASH, and to analyze and discuss some key variables that may interfere with this evaluation, such as host-, environment-, and heritability-related factors regulating vitamin D synthesis and metabolism; definitions of deficient or optimal vitamin D status with respect to skeletal and nonskeletal outcomes including NAFLD/NASH; methods of measuring 25(OH)D; and methods of diagnosing NAFLD as well as quantifying adiposity, the cardinal link between vitamin D deficiency and NAFLD.

Chronic myeloid leukemia (CML) is a myeloproliferative disease caused due to translocation between chromosome 9 and 22 leading to a chimeric gene product known as Bcr-Abl. Bcr-Abl fusion protein has constitutively activated Abl tyrosine kinase activity which is responsible for the uncontrolled proliferation in CML The tyrosine kinase inhibitors (TKIs) such as Imatinib, Dasatinib, and Nilotinib are the current first-line treatments approved by the United States Food and Drug Administration (US FDA) for the treatment of the disease. Despite the spectacular progress made over the decade with the TKIs, patients develop resistance to these TKIs. In such cases, stem cell transplant therapy, which is limited by donor availability, is the only proven cure for the patients. This highlights the need for the development of new strategies for CML treatment. The Bcr-Abl point mutations, including the gatekeeper T315I mutations, are the principal cause for the development of resistance to TKIs. However, other mechanisms are also involved in the failure of TKI therapy. This review outlines the Bcr-Abl dependent and independent mechanism of TKIs resistance development and the strategies used to overcome drug resistance, such as the development of ATP site and allosteric site inhibitors. Binding mode and structural elements of Bcr-Abl inhibition are discussed with emphasis on pathways involved in this complex disease to determine alternative strategies and combination therapies.

Thiazolidine-2,4-dione (TZD) is one of the most frequently encountered heterocyclic rings which has been implicated in design and synthesis of entities for various pathogenic conditions including cancer. Since its discovery various substitutions at 5th position have been carried out and reviewed. Various substitutions at 5th position have led to generation of glitazones, whose target peroxisome proliferating activated receptor γ (PPARγ) was found decade after their discovery. Acidic hydrogen (-NH) of TZD is a prime pharmacophoric requirement for the activation of PPARγ. However, advanced in-silico techniques have helped to design compounds bearing substitutions at both methylene and –NH group of TZD, targeting range of enzymes involved in various pathological conditions viz., diabetes, hyperlipidemia, infectious disease, inflammation and cancer. The promising activities shown by methylene and N-substituted TZDs in above mentioned therapeutic areas, prompted us to collate the information which would help researchers to alter the structure of existing ligands and to design new TZD derivatives with better safety and efficacy profiles.