Despite the advancements in the development of anticancer agents, more effective and safer anticancer drugs still need to be developed as the current agents cause unwanted side effects and many patients have become drug resistant. 1,2,3-Triazoles, due to their remarkable biological potential, have received considerable attention in drug discovery for the development of anticancer agents. The present review article presents an overview of the recent advances in 1,2,3-triazole hybrids with anticancer potential over the last 2 years, their chemical structures, structure-activity relationships, and mechanisms of action, as well as insights into the docking studies.

1,2,3-Triazole hybrids as anticancer agents: A review.

In this review we compare and discuss results of compounds already reported as anticancer agents based on isatin-derivatives, metalated as well as non-metallated Isatin compounds can be obtained from plants, marine animals, and is also found in human fluids as a metabolite of amino acids Its derivatives include imines, hydrazones, thiosemicarbazones, among others, already focused on numerous anticancer studies Some of them have entered in pre-clinical and clinical tests as antiangiogenic compounds or inhibitors of crucial proteins As free ligands or coordinated to metal ions, such isatin derivatives showed promising antiproliferative properties against different cancer cells, targeting different biomolecules or organelles Binding to metal ions usually improves its biological properties, indicating a modulation by the metal and by the ligand in a synergistic process They also reveal diverse mechanisms of action, being able of binding DNA, generating reactive species that cause oxidative damage, and inhibiting selected proteins Strategies used to improve the efficiency and selectivity of these compounds comprise structural modification of the ligands, metalation with different ions, syntheses of mononuclear and dinuclear species, and use of inserted or anchored compounds in selected drug delivery systems

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Anticancer Compounds Based on Isatin-Derivatives: Strategies to Ameliorate Selectivity and Efficiency.

Lung cancer is the most common malignancy and leads to around one-quarter of all cancer deaths. Great advances have been achieved in the treatment of lung cancer with novel anticancer agents and improved technology. However, morbidity and mortality rates remain extremely high, calling for an urgent need to develop novel anti-lung cancer agents. 1,2,3-Triazole could be readily interact with diverse enzymes and receptors in organisms through weak interaction. 1,2,3-Triazole not only can be acted as a linker to tether different pharmacophores, but also can serve as a pharmacophore. This review aims to summarize the recent advances in 1,2,3-triazole-containing compounds with anti-lung cancer potential, and their structure-activity relationship (SAR) together with mechanisms of action is also discussed to pave the way for the further rational development of novel anti-lung cancer candidates.

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1,2,3-Triazole-Containing Compounds as Anti-Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure-Activity Relationship.

Current status of carbazole hybrids as anticancer agents.

The drug resistance and low specificity of current available chemotherapeutics to cancer cells are the main reasons responsible for the failure of cancer chemotherapy and remain dramatic challenges for cancer therapy, creating an urgent need to develop novel anticancer agents. Carbazole nucleus, widely distributed in nature, is a predominant feature of a vast array of biologically active compounds. Carbazole derivatives exhibited potential antiproliferative activity against different cancer cell lines by diverse mechanisms, inclusive of arrest cell cycle and induce apoptosis, and several anticancer agents are carbazole-based compounds. Thus, carbazole derivatives represent a fertile source for discovery of novel anticancer therapeutic agents. Over the past several years, a variety of carbazole hybrids have been developed as potential anticancer agents. The present review focuses on the recent progress, from 2016 until now, in knowledge on anticancer properties, structure-activity relationships and mechanisms of action of carbazole hybrids to provide a basis for development of relevant therapeutic agents. 

Current status of carbazole hybrids as anticancer agents

Indole alkaloids, which are abundant in nature, are a significant source of pharmacologically active compounds. Indole alkaloids have the potential to exert anticancer activity via various antiproliferative mechanisms, and some of them, such as Vinblastine and Vincristinem, have already used in clinics or under clinical evaluations for the treatment of cancers. Therefore, indole alkaloids occupy an important position in the discovery of novel anticancer agents. This review emphasizes the recent development of indole alkaloids as potential anticancer agents, their structure-activity relationship, and mechanisms of action covering the articles published from 2015 to 2020.

Indole Alkaloids with Potential Anticancer Activity

Cancer, which has been cursed for human beings for long time is considered as one of the leading causes of morbidity and mortality across the world. In spite of different types of treatments available, chemotherapy is still deemed as a favored treatment for the cancer. Unfortunately, many currently accessible anticancer agents have developed multidrug resistance along with fatal adverse effects. Therefore, intensive efforts have been made to seek for new active drugs with improved anticancer efficacy and reduced adverse effects. In recent years, the emergence of heterocyclic ring-containing anticancer agents has gained a great deal of attention among medicinal chemists. 1,3- oxazole is a versatile heterocyclic compound, and its derivatives possess broad-spectrum pharmacological properties, including anticancer activity against both drug-susceptible, drug-resistant and even multidrug-resistant cancer cell lines through multiple mechanisms. Thus, the 1,3-oxazole moiety is a useful template for the development of novel anticancer agents. This review will provide a comprehensive overview of the recent advances on 1,3-oxazole derivatives with potential therapeutic applications as anticancer agents, focus on the chemical structures, anticancer activity, and mechanisms of action.

Current Scenario of 1,3-oxazole Derivatives for Anticancer Activity.

Aims To explore more active fluoroquinolone anticancer candidates. Background Cancer which can affect almost any part of the body, is most striking and deadliest disease. It is estimated that around one in five people globally develop cancer during their lifetime, and approximately 10% people eventually die from this disease, and 18.1 million new cancer cases with 9.6 million deaths occurred in 2018. The anticancer agents play an intriguingly role in fighting against cancer, and above 100 drugs have already been marketed for this purpose. However, the major drawback of current accessible anticancer agents is the low specificity which results in many side effects. Moreover, cancer cells have already generated resistance to almost all available drugs, creating an urgent need to novel anticancer agents with high specificity and great efficiency especially towards drug-resistant cancers. Quinolone and isatin derivatives were reported to possess promising anticancer activity, high specificity, and relatively few side effects. Currently, several quinolone and isatin derivatives such as Voreloxin, Quarfloxin, AT-3639, Semaxanib, Sunitinib and Nintedanib have already been introduced in clinical practice or under evaluations for the treatment of cancer including drug-resistant cancers, revealing their potential as novel anticancer agents. Hybrid molecules have the potential to increase the specificity, improve the efficiency, and overcome the drug resistance, so hybridization is a promising strategy in the drug discovery. Some of the moxifloxacin-isatin hybrids exhibited considerable activity against various cancer cells even drug-resistant cells, so it is conceivable that hybridization of quinolone and isatin moieties may provide novel anticancer candidates. The structure-activity relationships (SARs) demonstrated that the linkers between quinolone and isatin skeletons were critical for the biological activity, and 1,2,3-triazole could exert various noncovalent interactions with biological targets, so introduction of 1,2,3-triazole as the linker between the two moieties may provide more efficient anticancer candidates. Objective To explore more active fluoroquinolone anticancer candidates and enrich the structureactivity relationships of fluoroquinolone-isatin hybrids. Methods The synthesized moxifloxacin-isatin hybrids 5a-c, 6a-g and 13a-d were assessed for their anticancer activities against liver cancer cells HepG2, breast cancer cells MCF-7, MCF-7/DOX, prostate cancer cells DU-145 and MDR DU-145 by MTT assay. Hybrid 5b was selected for further evaluation of its tubulin polymerization inhibitory activity with combretastatin A-4 as comparison. Result Most of the synthesized hybrids were active against the tested cancer cell lines, and the most active hybrid 5b (IC50: 31.3-76.8 μM) was more potent than vorinostat (IC50: 96.7->100 μM), demonstrating moxifloxacin-isatin hybrids are potential anticancer candidates. Conclusion The mechanism study revealed that inhibition of tubulin polymerization is at least one of the mechanisms of action for this kind of hybrids. Other: The structure-activity relationship was summarized for further rational design of more efficient anticancer candidates.

Moxifloxacin-isatin Hybrids Tethered by 1,2,3-triazole and their Anticancer Activities.

AIM Development of 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)- thione hybrids as potential dual-acting mechanism anticancer agent to overcome the drug resistance. BACKGROUND Chemotherapy is an essential tool for the treatment of lung and female breast cancers, and numerous anticancer agents have been launched for this purpose. However, the clinical outcomes of chemotherapy are usually far from satisfactory due to the side effects and resistance to chemotherapeutic drugs. Thus, it is urgent to develop novel anti-lung and anti-breast cancer agents. OBJECTIVE The primary objective of this study was to evaluate the potential of bis-isatin scaffolds with alkyl/ether linkers between the two isatin moieties against different human breast cancer cell lines including A549, MCF-7 and their drug-resistant counterparts A549/CDDP, MCF-7/ADM cells. METHODS The 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-(4-methyl/phenyl/benzyl-3-aryl)-1,2,4- triazole-5(4H)-thione hybrids were screened for their in vitro activity against drug-sensitive lung (A549), breast (MCF-7) and their drug-resistant counterparts A549/CDDP (cisplatin-resistant), MCF- 7/ADM (doxorubicin-resistant) cancer cell lines by MTT assay. The inhibitory activity of these hybrids against topoisomerase II and EGFR was also evaluated to investigate the potential mechanism of action of these hybrids. RESULTS The most prominent hybrid 7k (IC50: 37.28-49.05 µM) was comparable to Vorinostat against A549 and A549/CDDP lung cancer cells, and was 2.79-2.94 times more active than Vorinostat against MCF-7 and MCF-7/ADM breast cancer cell lines. Moreover, hybrid 7k (IC50: 8.6 and 16.4 µM) also demonstrated dual inhibition against topoisomerase II and EGFR. CONCLUSION The 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)-thione hybrids possess equally activity against both drug-sensitive cancer cells and their drug-resistant counterparts, and the majority of them were no inferior to the reference Vorinostat. The mechanistic study revealed that these hybrids could inhibit both topoisomerase II and EGFR, so these hybrids can be developed as dual-acting mechanism anticancer agents.

The In Vitro Anticancer Activity and Potential Mechanism of Action of 1-[(1R,2S)-2-fluorocyclopropyl]Ciprofloxacin-(4-methyl/phenyl/benzyl-3- aryl)-1,2,4-triazole-5(4H)-thione Hybrids.

Aims A series of 8-methoxy ciprofloxacin- hydrazone/acylhydrazone hybrids were evaluated for their activity against a panel of cancer cell lines including HepG2 liver cancer cells, MCF-7, doxorubicin- resistant MCF-7 (MCF-7/DOX) breast cancer cells, DU-145 and multidrug-resistant DU145 (MDR DU-145) prostate cancer cells to seek for novel anticancer agents. Background Ciprofloxacin with excellent pharmacokinetic properties as well as few side effects, is one of the most common used antibacterial agents. Notably, Ciprofloxacin could induce cancer cells apoptosis, and cell cycle arrest at the S/G2 stage. The structure-activity relationship reveals that the introduction of the methoxy group into the C-8 position of the fluoroquinolone moiety has resulted in a greater binding affinity to the binding site, and 8-methoxy ciprofloxacin derivatives have proved a variety of biological activities even against drug-resistant organisms. However, to the best of our current knowledge, there are no studies that have reported the anticancer activity of 8-methoxy ciprofloxacin derivatives so far. Furthermore, many fluoroquinolone-hydrazone/acylhydrazone hybrids possess promising anticancer activity. Thus, it is rational to screen the anticancer activity of 8-methoxy ciprofloxacin derivatives. Objective To enrich the structure-activity relationship and provide new anticancer candidates for further investigations. Methods The desired 8-methoxy ciprofloxacin-hydrazone/acylhydrazone hybrids 5 and 6 were screened for their in vitro anticancer activity against liver cancer cells HepG2, breast cancer cells MCF-7, MCF7/DOX, prostate cancer cells DU-145 and MDR DU-145 by MTT assay. Results Some of 8-methoxy ciprofloxacin-hydrazone hybrids showed potential activity against HepG2, MCF-7, MCF-7/DOX, DU-145 and MDR DU-145 cancer cell lines, low cytotoxicity towards VERO cells and promising inhibitory activity on tubulin polymerization. Conclusion Compounds 5d and 5f showed promising anticancer activity, low cytotoxicity, and potential tubulin polymerization inhibitory activity, were worthy of investigation. Other: The structure-activity relationship was enriched.

Zhi Xu

Papers

Indole Alkaloids with Potential Anticancer Activity

Current Scenario of 1,3-oxazole Derivatives for Anticancer Activity.

Moxifloxacin-isatin Hybrids Tethered by 1,2,3-triazole and their Anticancer Activities.

The In Vitro Anticancer Activity and Potential Mechanism of Action of 1-[(1R,2S)-2-fluorocyclopropyl]Ciprofloxacin-(4-methyl/phenyl/benzyl-3- aryl)-1,2,4-triazole-5(4H)-thione Hybrids.

Antiproliferative Activity of 8-methoxy Ciprofloxacin-Hydrozone/Acylhydrazone Scaffolds.