Recent development of imidazole derivatives as potential anticancer agents

Cancer, one of the key health problems globally, is a group of related diseases that share a number of characteristics primarily the uncontrolled growth and invasive to surrounding tissues. Chemotherapy is one of the ways for the treatment of cancer which uses one or more anticancer agents as per chemotherapy regimen. Limitations of most anticancer drugs due to a variety of reasons such as serious side effects, drug resistance, lack of sensitivity and efficacy etc. generate the necessity towards the designing of novel anticancer lead molecules. In this regard, the synthesis of biologically active heterocyclic molecules is an appealing research area. Among heterocyclic compounds, nitrogen containing heterocyclic molecules has fascinated tremendous consideration due to broad range of pharmaceutical activity. Imidazoles, extensively present in natural products as well as synthetic molecules, have two nitrogen atoms, and are five membered heterocyclic rings. Because of their countless physiological and pharmacological characteristics, medicinal chemists are enthused to design and synthesize new imidazole derivatives with improved pharmacodynamic and pharmacokinetic properties. The aim of this present chapter is to discuss the synthesis, chemistry, pharmacological activity, and scope of imidazole-based molecules in anticancer drug development. Finally, we have discussed the current challenges and future perspectives of imidazole-based derivatives in anticancer drug development.

Recent Trends in Tubulin-Binding Combretastatin A-4 Analogs for Anticancer Drug Development

: Although significant progress over several decades has been evidenced in cancer therapy, there still remains a need for the development of novel and effective therapeutic strategies to treat several relapsed and intractable cancers. In this regard, tubulin protein has become one of the efficient and major targets for anticancer drug discovery. Considering the antimitotic ability, several tubulin inhibitors have been developed to act against various cancers. Among various tubulin inhibitors available, combretastatin-A4 (CA-4), a naturally occurring lead molecule, offers exceptional cytotoxicity (including the drug-resistant cell lines) and antivascular effects. Although CA-4 offers exceptional therapeutic efficacy, several new advancements have been proposed, such as the structural modification via A and B rings, as well as cis-olefinic bridging, which provide highly efficient analogs with improved tubulin-binding efficiency to meet the anticancer drug development requirements. This review systematically emphasizes the recent trends and latest developments in the anticancer drug design & discovery, using CA-4 analogs as the tubulin inhibiting agents, highlighting their structure-activity relationships (SAR) and resultant pharmacological efficacies.

MicroRNA as an Important Target for Anticancer Drug Development

Cancer has become the second greatest cause of death worldwide. Although there are several different classes of anticancer drugs that are available in clinic, some tough issues like side-effects and low efficacy still need to dissolve. Therefore, there remains an urgent need to discover and develop more effective anticancer drugs. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression by inhibiting mRNA translation or reducing the stability of mRNA. An abnormal miRNA expression profile was found to exist widely in cancer cell, which induces limitless replicative potential and evading apoptosis. MiRNAs function as oncogenes (oncomiRs) or tumor suppressors during tumor development and progression. It was shown that regulation of specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways, and reverse the phenotypes in cancer cells. The miRNA hence provides an attractive target for anticancer drug development. In this review, we will summarize the latest publications on the role of miRNA in anticancer therapeutics and briefly describe the relationship between abnormal miRNAs and tumorigenesis. The potential of miRNA-based therapeutics for anticancer treatment has been critically discussed. And the current strategies in designing miRNA targeting therapeutics are described in detail. Finally, the current challenges and future perspectives of miRNA-based therapy are conferred.

Exploring the selectivity of guanine scaffold in anticancer drug development by computational repurposing approach

Drug repurposing is one of the modern techniques used in the drug discovery to find out the new targets for existing drugs. Insilico methods have a major role in this approach. We used 60 FDA approved antiviral drugs reported in the last 50 years to screen against different cancer cell receptors. The thirteen compounds selected after virtual screening are analyzed for their druggability based on ADMET parameters and found the selectivity of guanine derivatives—didanosine, entecavir, acyclovir, valganciclovir, penciclovir, ganciclovir and valacyclovir as suitable candidates. The pharmacophore model, AARR, suggested based on the common feature alignment, shows that the two fused rings as in guanine and two acceptors-one from keto-oxygen (A5) and other from the substituent attached to nitrogen of imidazole ring (A4) give the druggability to the guanine derivatives. The NBO analysis on N9 is indicative of charge distribution from the ring to substituents, which results in delocalization of negative character in most of the ligands. The molecular dynamics simulations also pointed out the importance of guanine scaffold, which stabilizes the ligands inside the binding pocket of the receptor. All these results are indicative of the selectivity of guanine scaffold in anticancer drug development, especially as PARP1 inhibitors in breast, ovarian and prostate cancer. As these seven molecules are already approved by FDA, we can safely go for further preclinical trials.

Targeting Protein Kinases Degradation by PROTACs

Kinase dysregulation is greatly associated with cell proliferation, migration and survival, indicating the importance of kinases as therapeutic targets for anticancer drug development. However, traditional kinase inhibitors binding to catalytic or allosteric sites are associated with significant challenges. The emergence of resistance and targeting difficult-to-degrade and multi-domain proteins are significant limiting factors affecting the efficacy of targeted anticancer drugs. The next-generation treatment approaches seem to have overcome these concerns, and the use of proteolysis targeting chimera (PROTAC) technology is one such method. PROTACs bind to proteins of interest and recruit E3 ligase for degrading the whole target protein via the ubiquitin-proteasome pathway. This review provides a detailed summary of the most recent signs of progress in PROTACs targeting different kinases, primarily focusing on new chemical entities in medicinal chemistry.

A REVIEW ON ANTICANCER POTENTIAL OF SOME PYRANOCARBAZOLE ALKALOIDS AND ITS DERIVATIVES

Pyranocarbazole alkaloids isolated from natural sources various plant parts of the flower-bearing geneses plants Murraya, Clausena, Glycosmis, species belongs to family Rutaceae. These pyranocarbazole alkaloids showed potential anticancer activities on various cancer cell lines. In this review, we discussed the anticancer potential of pyranocarbazole alkaloids like Mahanine, Koenimbine, Koenidine, Murrayozoline, Girinimbine, Mahanimbine mainly on the basis of reported review literature. In particular, we discuss in vitro anticancer activities of these pyranocarbazole alkaloids and its derivatives on various cancer cell lines, plausible target, also in vivo activity if reported in literature discussed. These pyranocarbazole structure-based alkaloids showed very interesting anticancer profile. This review can be fruitful for further investigation of these pyranocarbazole alkaloids as anticancer drug development against various types of cancer with minimum side effects.

Selectivity of Guanine Scaffold in Anticancer Drug Development: A Computational Repurposing Approach

Drug repurposing is one of the modern techniques used in the drug discovery to find out the new targets for existing drugs. Insilico methods have a major role in this approach. We used 60 FDA approved antiviral drugs reported in the last 50 years to screen against different cancer cell receptors. The thirteen compounds selected after virtual screening are analyzed for their druggability based on ADMET parameters and found the selectivity of guanine derivatives- didanosine, entecavir, acyclovir, valganciclovir, penciclovir, ganciclovir and valacyclovir as suitable candidates. The pharmacophore model, AARR, suggested based on the common feature alignment, shows that the two fused rings as in guanine and two acceptors-one from keto-oxygen(A5) and other from the substituent attached to nitrogen of imidazole ring(A4) give the druggability to the guanine derivatives. The NBO analysis on N9 is indicative of charge distribution from the ring to substituents, which results in delocalization of negative character in most of the ligands. The molecular dynamics simulations also pointed out the importance of guanine scaffold, which stabilizes the ligands inside the binding pocket of the receptor. All these results are indicative of the selectivity of guanine scaffold in anticancer drug development, especially as PARP1 inhibitors in breast, ovarian and prostate cancer. As these seven molecules are already approved by FDA, we can safely go for further preclinical trials.