Precision Deuteration in Search of Anticancer Agents: Approaches to Cancer Drug Discovery.

Cancer chemotherapy has been shifted from conventional cytotoxic drug therapy to selective and target-specific therapy after the findings about DNA changes and proteins that are responsible for cancer. A large number of newer drugs were discovered as targeted therapy for particular types of neoplastic disease. The initial discovery includes the development of the first in the category, imatinib, a Bcr-Abl tyrosine kinase inhibitor (TKI) for the treatment of chronic myelocytic leukemia in 2001. But the joy did not last for long as the drug developed a point mutation within the ABL1 kinase domain of BCR-ABL1, which subsequently led to the discovery of many other TKIs. Resistance was observed for newer TKIs a few years after their launching, but the use of TKIs in life-threatening cancer therapy is considered as far better compared with the risks of disease because of its target specificity and hence less toxicity. In search of a better anticancer agent, the physiochemical properties of the lead molecule have been modified for its efficacy toward disease and delay in the development of resistance. Deuteration in the drug molecule is one of such modifications that alter the pharmacokinetic properties, generally its metabolism, as compared with its pharmacodynamic effects. Precision deuteration in many anticancer drugs has been carried out to search for better drugs for cancer. In this review, the majority of anticancer drugs and molecules for which deuteration was applied to get better anticancer molecules were discussed. This review will provide a complete guide about the benefits of deuteration in cancer chemotherapy.

Novel Multitarget Directed Triazinoindole Derivatives as Anti-Alzheimer Agents.

The multifaceted nature of Alzheimer's disease (AD) demands treatment with multitarget-directed ligands (MTDLs) to confront the key pathological aberrations. A novel series of triazinoindole derivatives were designed and synthesized. In vitro studies revealed that all the compounds showed moderate to good anticholinesterase activity; the most active compound 23e showed an IC50 value of 0.56 ± 0.02 µM for AChE and an IC50 value of 1.17 ± 0.09 µM for BuChE. These derivatives are also endowed with potent antioxidant activity. To understand the plausible binding mode of the compound 23e, molecular docking studies and molecular dynamics simulation studies were performed, and the results indicated significant interactions of 23e within the active sites of AChE as well as BuChE. Compound 23e successfully diminished H2O2-induced oxidative stress in SH-SY5Y cells and displayed excellent neuroprotective activity against H2O2 as well as Aß-induced toxicity in SH-SY5Y cells in a concentration dependent manner. Furthermore, it did not show any significant toxicity in neuronal SH-SY5Y cells in the cytotoxicity assay. Compound 23e did not show any acute toxicity in rats at doses up to 2000 mg/kg, and it significantly reversed scopolamine-induced memory deficit in mice model. Additionally, compound 23e showed notable in silico ADMET properties. Taken collectively, these findings project compound 23e as a potential balanced MTDL in the evolution process of novel anti-AD drugs.

Synthesis and Biological Evaluation of Novel Multi-target-Directed Benzazepines Against Excitotoxicity.

Excitotoxicty, a key pathogenic event is characteristic of the onset and development of neurodegeneration. The glutamatergic neurotransmission mediated through different glutamate receptor subtypes plays a pivotal role in the onset of excitotoxicity. The role of NMDA receptor (NMDAR), a glutamate receptor subtype, has been well established in the excitotoxicity pathogenesis. NMDAR overactivation triggers excessive calcium influx resulting in excitotoxic neuronal cell death. In the present study, a series of benzazepine derivatives, with the core structure of 3-methyltetrahydro-3H-benzazepin-2-one, were synthesised in our laboratory and their NMDAR antagonist activity was determined against NMDA-induced excitotoxicity using SH-SY5Y cells. In order to assess the multi-target-directed potential of the synthesised compounds, Aß1-42 aggregation inhibitory activity of the most potent benzazepines was evaluated using thioflavin T (ThT) and Congo red (CR) binding assays as Aß also imparts toxicity, at least in part, through NMDAR overactivation. Furthermore, neuroprotective, free radical scavenging, anti-oxidant and anti-apoptotic activities of the two potential test compounds (7 and 14) were evaluated using primary rat hippocampal neuronal culture against Aß1-42-induced toxicity. Finally, in vivo neuroprotective potential of 7 and 14 was assessed using intracerebroventricular (ICV) rat model of Aß1-42-induced toxicity. All of the synthesised benzazepines have shown significant neuroprotection against NMDA-induced excitotoxicity. The most potent compound (14) showed relatively higher affinity for the glycine binding site as compared with the glutamate binding site of NMDAR in the molecular docking studies. 7 and 14 have been shown experimentally to abrogate Aß1-42 aggregation efficiently. Additionally, 7 and 14 showed significant neuroprotective, free radical scavenging, anti-oxidant and anti-apoptotic properties in different in vitro and in vivo experimental models. Finally, 7 and 14 attenuated Aß1-42-induced tau phosphorylation by abrogating activation of tau kinases, i.e. MAPK and GSK-3ß. Thus, the results revealed multi-target-directed potential of some of the synthesised novel benzazepines against excitotoxicity.