Key Heterocyclic Cores for Smart Anticancer Drug–Design Part II

With the second-highest cause of mortality in the world, cancer becomes a major threat around the globe. In the last few decades, heterocyclic compounds, obtained naturally or synthetically, have been developed as a potential scaffold for developing many anticancer drugs. Heterocyclic compounds due to heteroatoms such as oxygen, nitrogen and sulphur can be employed as hydrogen bond donors as well as acceptors. Thus, they can bind suitably to pharmacological targets and receptors via intermolecular H-bonds more effectively, giving pharmacological effects. They can also alter liposolubility, hence the aqueous solubility of drug molecules to achieve remarkable pharmacotherapeutic properties. These heterocyclic leads exert the anticancer activity by a distinctive mechanism such as inhibiting Bcl-2, Mcl-1 proteins (induce apoptosis), inhibiting PIM proteins (hinder the cellular process and signal transduction in cells), inhibiting DNA topoisomerase, inhibiting aromatase (inhibit replication and transcription), modulating epigenetic mechanisms (inhibit histone deacetylase/HDAC) and inhibiting cellular mitosis (tubulin inhibitors).The current chapter aims to describe these promising anticancer targets. The novel targets are also illustrated with a pictorial presentation to understand heterocyclic drugs action on various cancer targets. This chapter will facilitate researchers, pharmacologists, and medicinal chemists in the understanding mechanism of heterocyclic drugs, which can help develop new anticancer agents.

The severity, prevalence, and complexity of cancer do not need any introduction at present. The coumarin scaffold has been explored intermittently for its anti-cancer potential for a long time, and continuous research is further in progress. The concept of molecular hybridization has opened new doors towards the design and development of therapeutic candidates, capable of binding to multiple targets. This has been proven to be a promising approach for diseases with complex pathophysiology involving a variety of targets. In this direction, several research groups have explored the therapeutic potentials of coumarin and its derivatives against cancer. Coumarin possesses multiple sites for substitution/tethering/fusion, providing ease for constructing coumarin hybrid molecules. Coumarin and its derivatives have the ability to exert anti-cancer activity by interacting/binding with several targets, including aromatase, sulphatase, protein kinases, telomerase, carbonic anhydrase, caspases, SERD (selective estrogen receptor downregulators), tubulin, phosphoinositide 3- kinases (PI3K), topoisomerase and hormones. These targets are involved in complex pathological events during the development of cancer. Several heterocyclic moieties beyond coumarin are also capable of binding to one or more of these targets. Therefore, conjuring such a heterocycle with coumarin moiety is an ideal approach to target more than one target simultaneously. In this chapter, the authors have highlighted important targets along with their significance in the development of cancer. A description of reported potent anti-cancer coumarin hybrids (in the past five years) inhibiting/interacting with particular targets has been provided. Although there is a tremendous advancement in developing hybrid molecules against cancer, still no suitable candidate has been launched in the market for a long time. So, further clinical and toxicological investigations on reported lead molecules should be carried out on priority.

Cancer is a widespread disease worldwide. Researchers and scientists have been giving much attention to the drug design and drug discovery of nitrogen (N) and sulfur (S)-based heterocyclic compounds in the last decade. These heteroatoms containing heterocyclic compounds have an imperative role in medicinal chemistry in developing new anticancer drugs. These N and S-based heterocyclic compounds such as pyrrole, quinazoline, thiadiazole, and quinoline are widely used in the rational drug design for anticancer drugs with a favorable therapeutic index. They inhibit the cancerous cells by different mechanisms like inhibiting FGFR, VEGFR, EGFR receptors and inducing apoptosis. They also act as a tyrosine kinase inhibitor, dihydrofolate reductase inhibitor, pancreatic ductal adenocarcinoma inhibitor, and PI3K inhibitor. This chapter highlights the SAR study of recent literature (2016-2020) in which N and S heterocyclic compounds are present as core structures in molecules. This chapter also emphasizes the benefits of hybrid molecules acting on multiple target mechanisms. In the future, N and S- based heterocyclic compounds will be essential lead compounds for the designing of new anticancer drugs. 

 In the current era, numerous anticancer drugs are available with potential pharmacological activity. Still, issues like multi-drug resistance, toxicity, solubility etc., were in existence, which finally decreases the overall therapeutic value of indices of the drug molecule. Therefore, in search of new anticancer agents to fight against cancer is not an ending process. Keeping this in view, aromatic diazole heterocyclic nucleus named imidazole was proved with quite promising health benefits. The imidazole nucleus possesses numerous pharmacological activities. Thus, its derivatives/analogs have occupied a distinctive position in medicinal chemistry due to the incorporation of the heterocyclic nucleus, imidazole, to develop the new synthetic strategy in the significant drug discovery process. In addition to this, the significant therapeutic potential of the imidazole containing agents have triggered the medicinal chemist to develop a large number of novel anticancer compounds with a low toxicity profile. This chapter aims ornately pronounced the therapeutic voyage of imidazole and its analogs as anticancer.

The morpholine ring is considered the most preferred and versatile heterocylic ring in medicinal chemistry due to its distinctive mechanistic activities that give it various biological activities. The eminence of the morpholine ring to modulate the pharmacokinetic properties of the compound, further makes it a fundamental pharmacophore in developing lead molecules. Multi-drug resistance in cancer leads to discovering selective and potent chemotherapeutic agents. Researchers are designing and synthesizing morpholine derivatives as potential anticancer drugs those act by targeting various signaling pathways driven by various protein kinases in the cell, i.e. Ras-Raf-MEK-ERK (ERK) and PI3K/Akt/mTOR, thereby inhibiting cell proliferation and growth. The potency of natural and synthetic derivatives of morpholine makes it a drug of choice for cancer treatment. Many of the morpholine containing anticancer drugs are under clinical trials. Hence, morpholine ring synthesis also becomes a central target for various scientists using green synthesis by straightforward one-step methods. A substantial literature is available on synthetic techniques of morpholine and substituted morpholine. The present chapter updates diverse new synthetic strategies of the morpholine ring and morpholine derivatives with potent anticancer activity. The chapter will also highlight the clinical data of morpholine derivatives with anticancer activity and mechanism of action. The latest information on novel anticancer morpholine derivatives with structural activity relationship (SAR) is also included. This chapter provides information about the necessary structural modifications required in drugs' chemical structure and contribute to the anticancer drug discovery program.

Cancer is one of the biggest health-care challenges to human race and requires an innovative treatment strategy for cure. Undesirable side effects and rapid development of resistance to the conventional therapy have made the scenario more alarming. The chemical diversity of the natural products is immense and therefore is an amazing reserve for the finding of novel anticancer agents. Further, natural products have played a significant role in providing the novel and effective treatment inputs in the field on anticancer research. The compounds obtained from these sources range from a simple peptide, Dolastatin 10, to a complex polyether, Halichonrin B. Natural products have been source of many anticancer agents that are being used in clinical or pre-clinical trials. Further, many compounds derived from natural products have shown potential to be future anticancer agents. Due to their actions on numerous targets natural products are considered ideal for anticancer drug development. Further, their selectivity towards cancer cells is more in comparison to conventional treatment, so their toxicity is lower. This chapter summarizes the progress and ongoing developments in natural products and their analogs as anticancer agents. The challenges and future prospects of natural products based anticancer agents are also discussed.