Mini Reviews in Medicinal Chemistry - Volume 18, Issue 19, 2018

Aporphine alkaloids, characterized by a heterocyclic aromatic basic skeleton, are known from different organisms and exhibit various biological activities: anti-tumor, anti-viral, anti-microbial, anti-inflammatory etc. The review gives information which provides an overview of the latest progress in the structural diversity and the biological activity of the aporphine alkaloids with their derivatives isolated from natural resource in recent years. Additionally, the synthetic approaches of aporphine alkaloids have also been reviewed.

Opioid analgesics, such as morphine, are widely employed in the treatment of moderate to severe pain. However, they are notorious for abuse liability and respiratory depression. Therefore circumventing the side effects, such as euphoria, addiction, respiratory depression and gastrointestinal adverse reactions, is of extensive importance. Recently, a large number of research results have revealed that such morphine-like side effects are not inevitable, and they focus on the novel approaches to disconnecting the analgesics from adverse effects. In this review, we mainly discuss the approaches including biasing the GPCRs over β-arrestin2 recruitment (TRV130, PZM21, HS665), the positive allosteric modulators of the MOR (BMS-986122) and multiple agonists of opioid receptors subtypes (SNC80, DPI-125). Besides these, we also introduce the key protein sites of MOR and β-arrestin2 recruitment briefly.

Farnesyl Transferase is a hetero-dimer transferase that targets Ras proteins and attaches a farnesyl group to it. This Ras protein, on localization to the cell membrane, has the ability to induce activation of various growth and proliferation pathways of the cell. Over-activation of mutated Ras may lead to the development of cancer. Farnesyl Transferase catalyses the initial step in the posttranslational modification of normal as well as mutated Ras gene, thus facilitating its tethering to the cell membrane. Inhibition of Farnesyl Transferase is the main step in restricting the activity of mutant Ras protein. Thus the above enzyme has emerged as a novel target for anti-cancer agents. Here we review the role of Farnesyl Transferase in tumorigenesis and various compounds of synthetic and natural origin acting as Farnesyl Transferase inhibitors as potential anti-cancer agents.

Background: Harmalol, a beta carboline alkaloid, shows remarkable importance in the contemporary biomedical research and drug discovery programs. With time, there is emerging interest in search for better anti-cancer drugs of plant origin with high activity and lower toxicity. Most of the chemotherapeutic agents due to their non-specific target and toxicity on active healthy cells, use is often restricted, necessitating search for newer drugs having greater potentiality. Objective: The review highlighted the interaction of harmalol with nucleic acids of different motifs as sole target biomolecules and in vitro cytotoxicity of the alkaloid in human cancer cell lines with special emphasis on its apoptotic induction ability. Methods: Binding study and in vitro cytotoxicity was performed using several biophysical techniques and biochemical assays, respectively. Results: Data from competition dialysis, UV and fluorescence spectroscopic analysis, circular dichroism, viscometry and isothermal calorimetry shows binding and interaction of harmalol with several natural and synthetic nucleic acids, both DNA and RNA, of different motifs. Furthermore, apoptotic hallmarks like internucleosomal DNA fragmentation, membrane blebbing, cell shrinkage, chromatin condensation, change of mitochondrial membrane potential, comet tail formation and ROS (reactive oxygen species) dependent cytotoxicity being analyzed in the harmalol treated cancer cells. Conclusion: These results stating the therapeutic role of harmalol, will lead to the interesting knowledge on the cytotoxicity, mode, mechanism, specificity of binding and correlation between structural aspects and energetics enabling a complete set of guidelines for design of new drugs.

Pyrrole-2-aminoimidazole compounds are found in marine organisms, mainly as secondary metabolites in various marine sponges. Studies of natural pyrrole-2-aminoimidazole compounds showed that they possess different pharmacological properties, such as antimicrobial, antibiofilm, immunosuppressive and anticancer activities. Many analogs of the natural compounds have been synthesized to improve their biological activities. This review focuses on the antibacterial and antibiofilm potentials of natural pyrrole-2-aminoimidazoles and their synthetic analogs and derivatives, as well as on the structure-activity relationships of the most promising compounds. Known molecular targets of these compounds in bacterial cells are also described here, as is the synergistic activity of the pyrrole- 2-aminoimidazoles and conventional antibiotics.

Poly(ADP-ribose)polymerase, member 14 (PARP14, alternatively named ARTD8, BAL2, and COAST6) is an intracellular mono(ADP-ribosyl) transferase. PARP14 transfers a negatively charged ADP-ribose unit from a donor NAD+ molecule onto a target protein, post-translationally. PARP14's domain architecture consists of three macrodomains (Macro1, Macro2 and Macro3), a WWE domain and an ARTD (or catalytic domain). The Macro2 and Macro3 domains bind ADPribose (ADPr) with high affinity, whereas the WWE domain stabilizes the protein structure by binding to ADPr derivatives. The catalytic domain is involved in binding the NAD+ and catalyzing the mono- ADP-ribosylation reaction. PARP14 has been identified as a possible anti-cancer and antiinflammatory target. Acting as a transcriptional co-activator for STAT6, PARP14 acts to promote the over activation of the Th2 immune response, thus promoting the metabolic change to an anaerobic state (Warburg effect) and activation of cell survival pathways through JNK2 and the PGI/AMF complex. These changes are consistent with the metabolic sophistication observed in cancer, and the immune imbalance in inflammatory diseases. Current literature on selective and unselective PARP14 inhibitors are reviewed and discussed. Although there is no evidence that selective PARP inhibitors would be advantageous we have proposed some strategies for future design of selective PARP14 inhibitors.

Background: Chemotherapy has become one of the methods that are being adopted to treat cancer. Coumarins, thiazoles and thiadiazoles are versatile synthetic scaffolds possessing wide spectrum of biological effects including potential anticancer activity. Objective: In the efforts to develop suitable anticancer drugs, medicinal chemists have focused on coumarin derivatives. A series of novel thiazole-pyranochromene and thiadiazole-pyranochromene derivatives were synthesized via heterocyclization of varies hydrazonoyl halides with methyl pyrano[3,2- g]chromen-3-yl)ethylidene)hydrazine-1-carbodithioate and pyrano[3,2-g]chromen-3-yl)ethylidene)- hydrazine-1-carbothioamide, respectively. Method: All the newly synthesized compounds have been characterized on the basis of elemental analysis and spectral data (IR, 1H and 13C NMR, Mass). Moreover, all the products were evaluated for their anticancer activity against HEPG2-1. Results: The results revealed that six new compounds showed promising anticancer activity. Conclusion: In the present paper, 3-acetyl-5-methoxy-8-methyl-2H,6H-pyrano[3,2-g]chromene-2,6- dione proved to be a useful precursor for synthesis of various 1,3-thiazoles and 1,2,4-thiadiazoles incorporating pyrano[3,2-g]chromene moiety as anticancer agents. The computational studies using MOE 2014.09 software are confirming the results in biological activity.