Identification of novel class of Triazolo-Thiadiazoles as potent inhibitors of human Heparanase and their anticancer activity

Expression and activity of heparanase, an endoglycosidase that cleaves heparan sulfate (HS) side chains of proteoglycans, is associated with progression and poor prognosis of many cancers which makes it an attractive drug target in cancer therapeutics

Nano-cuprous oxide catalyzed one-pot synthesis of a carbazole-based STAT3 inhibitor: a facile approach via intramolecular C–N bond formation reactions

In this study, we report the one-pot synthesis of substituted carbazole derivatives using nano cuprous oxide as a catalyst via intramolecular C–N bond forming reactions. Among the synthesized carbazoles, 3′-((3-acetyl-6-chloro-9H-carbazol-9-yl)methyl)-1{,}1′-biphenyl-2-carbonitrile (ACB) was identified as a lead antiproliferative agent against lung cancer cell lines A549 and LLC with an IC50 of 13.6 and 16.4 μM respectively. Furthermore{,} we found that the lead compound suppresses the constitutive phosphorylation of STAT3 (Tyr-705) in A549{,} HCC-2279 and H1975 cells. We analyzed the levels of phospho-STAT3 and LSD1 in the nuclear extract of ACB treated HCC-2279 cells to evaluate the transcriptional activity of STAT3. We found the downregulation of phospho-STAT3 without any change in the expression of LSD1 indicating that ACB downregulates the transcriptional activity of STAT3. Molecular docking analysis revealed that ACB makes a favorable interaction with Arg-609 and Ser-613 in the pTyr site of the SH2 domain of STAT3

Adamantyl-tethered-biphenylic compounds induce apoptosis in cancer cells by targeting Bcl homologs

Bcl homologs prominently contribute to apoptotic resistance in cancer cells and serve as molecular targets in treatment of various cancers. Herein, we report the synthesis of biphenyl-adamantane derivatives by a ligand free palladium on carbon based Suzuki reaction using diisopropylamine as a base for the coupling of adamantane based aryl chloride with a variety of aryl boronic acids. Among the biphenyl derivatives synthesized, compound 3′-(adamantan-1-yl)-4′-methoxy-1,1′-biphenyl-3-ol (AMB) displayed cytotoxic activity against hepatocellular carcinoma cell lines without significantly affecting the normal cell lines. Further, AMB caused increased accumulation of the HCC cells in subG1 phase, decreased the expression of Bcl-2, Bcl-xL, cyclin D1, caspase-3, survivin and increased the cleavage of PARP in a time-dependent manner. In silico molecular interaction studies between Bcl homologs and AMB showed that the biphenyl scaffold is predicted to form π–π interactions with Phe-101 and Tyr-105 and the adamantyl fragment is predicted to occupy another hydrophobic region in the kink region of the binding groove. In summary, we report on the synthesis and biological characterization of adamantyl-tethered biphenylic compounds that induce apoptosis in tumor cells most likely by targeting Bcl homologs

The Control of Heparanase Through the Use of Small Molecules

Despite the enormous progress made in recent years with antibodies, vaccines, antisense oligonucleotides, etc., the so-called “biological” approaches for tackling the control of various diseases, medicinal chemistry remains a bulwark to refer to for the development of new drugs. Also in the case of heparanase, medicinal chemistry has always been in the forefront to identify new inhibitors, through modification of natural macromolecules, e.g., sulfated polysaccharides like heparin, or of natural compounds isolated from bacteria or plants, or through rational design. In this chapter, the reader will find a detailed description of the most relevant small-molecule heparanase inhibitors reported so far in the scientific literature and in patent applications, with mention to the design strategy and to structure-activity relationships. Starting from heparanase inhibitors of natural origin and the attempts to improve their potency and selectivity, the reader will be guided through the major chemical classes of synthetic inhibitors, with representation of the structure of the most relevant compounds. The last paragraph is dedicated to a brief description of inhibitors that have reached clinical trials, highlighting their structure, mechanism, and improved derivatives