Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 18, Issue 1, 2018

Background & Objective: Cancer is one of the leading causes of death worldwide. In view of ever increasing number associated with cancer related death, there is an urgent need to find out a novel compound especially of natural origin (better efficacy, less or non-toxic and cost effective) that could serve against the treatment of all forms of cancer. Currently, available treatment options related to cancer have their certain limitations especially in the case of solid tumors. Method: In search of the natural anticancer compound, alkaloids, in general, have been exploited by the scientist working in this field of research. Among these alkaloids, azoles (secondary metabolite) have been significantly highlighted in literature because of their anticancer potential and better efficacy against various forms of cancer. Results: Their mechanism of action includes induction in the cleavage of poly-ADP ribose polymerase (PARP), induction of caspase 3 and caspase 9, modulation of nuclear factor kappa B, damage to DNA, cell cycle arrest at G1 and G2/M stage, apoptosis and c-Myb inhibition. In the current article, we have tried to cover various azoles especially from oxazoles, thiazoles and carbazoles class that have been reported for their anticancer potential. Conclusion: Based on our article, we believe that, soon, the scientific community will come up with certain azole which will work against cancer at large rather than a specific type of cancer.

Background: Histamine is an imidazolic compound performing a crucial function in the pathogenesis of inflammation. Several studies have also emphasized its pro-carcinogenic effect in colorectal cancer (CRC). Object: In fact, increased histamine levels have been observed in CRC and a decreased catabolism of this molecule is typical of colorectal adenomas. Additional data have demonstrated that CRC is characterized by an altered balance of histamine receptors (HRs); in fact, HR1 and HR4 are down-regulated in CRC, while HR2 is overexpressed. Method: Based on this evidence, we reviewed several studies investigating the role of HR2 antagonists (HR2A), such as cimetidine in CRC. Results: From a clinical point of view, HR2A may prolong the survival rates of patients with CRC, and a recent meta-analysis seems to confirm this finding. From a biological perspective, it has been demonstrated that HR2A could have a beneficial effect on CRC for many reasons: i) promotion of peri-tumoral lymphocyte growth and improvement of immune response against the tumor, ii) suppression of adhesion molecules which might favor metastasis, iii) anti-angiogenetic activity (reduction of VEGF), iv) increased production of some cytokines which may counteract tumor growth, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-10 and IL-15. On the contrary, HR1 antagonists did not demonstrate any beneficial effect on CRC. Therefore, it is presumable that histamine could be a relevant player in the development of CRC, but its effect might be mediated by an imperfect homeostasis of its receptors. Conclusion: In this scenario, HR2A could inhibit carcinogenesis whereas HR2 might act as a pro-carcinogenetic, while HR1 and HR4, being suppressed in CRC, may antagonize neoplastic development.

Cancer is a class of formidable disease with high degree of mortality. Despite much progress in chemotherapy, the problem of drug resistance has led to the search for newer leads with superior efficacy. 1,2,3- Triazoles are among a vast number of nitrogen containing heterocycles studied extensively as pharmacologically important scaffolds. Recently developed copper(I)-catalyzed cycloaddition reaction between organic azides and terminal alkynes yielding 1,4-disubstituted 1,2,3-triazoles has attracted considerable attention because it allows the construction of a vast array of 1,2,3-triazoles with significant potential in pharmaceutical chemistry. In this article, an attempt to summarize the wide range of anticancer agents derived from copper(I)-catalyzed azide alkyne cycloaddition reported by the authors worldwide, has been made. This review includes articles published from 2010 onwards and summarizes the recent progress on the development of 1,4-disubstituted 1H-1,2,3-triazoles as novel anticancer chemotypes with high therapeutic indices.

Background: A number of benzimidazole derivatives such as benomyl and carbendazim have been known for their potential role as agricultural fungicides. Simultaneously carbendazim has also been found to inhibit proliferation of mammalian tumor cells specifically drug and multidrug resistant cell lines. Objective: To understand the dual role of Carbendazim as a fungicide and an anticancer agent, the study has been planned referring to the earlier studies in literature. Results: Studies carried out with fungal and mammalian cells have highlighted the potential role of carbendazim in inhibiting proliferation of cells, thereby exhibiting therapeutic implications against cancer. Because of its promising preclinical antitumor activity, Carbendazim had undergone phase I clinical trials and is under further clinical investigations for the treatment of cancer. A number of theoretical interactions have been pinpointed. There are many anticancer drugs in the market, but their usefulness is limited because of drug resistance in a significant proportion of patients. The hunger for newer drugs drives anticancer drug discovery research on a global platform and requires innovations to ensure a sustainable pipeline of lead compounds. Conclusion: Current review highlights the dual role of carbendazim as a fungicide and an anticancer agent. Further, the harmful effects of carbendazim and emphasis upon the need for more pharmacokinetic studies and pharmacovigilance data to ascertain its clinical significance, have also been discussed.

Background: Cancer has gradually become one of the leading causes of death worldwide. The incidence of cancer among the population has increased alarmingly over the last two decades, primarily due to an increasing population of immune-compromised patients and the continuing rise in anti-cancer drug resistance. Azole found privileged structure in medicinal chemistry and pharmaceutical industry and also found to be showing antioxidant; antimicrobial, anthelmintic, anticancer, antiviral, anti-parasitic, anti-inflammatory, anti-HIV, and antihypertensive activities. Objective: In this review, we highlight some areas of current interest in context to azoles and their derivatives as potential chemotherapeutic agents and inhibitors. Method: A comprehensive literature search was performed for writing this review. An updated view on different derivatives of azoles and use in cancer management has been discussed. Results: Here we have discussed the present scenario of azoles and their derivatives as potential chemotherapeutic agents and inhibitors. Along with, the future perspectives of azoles in cancer prevention and treatment are also discussed. Conclusion: The information provided in this review might be useful to researchers in designing of novel and potent multifunctional azole analogues for the treatment of cancer and other multifactorial diseases.

Aims: The current study is focused on the design and synthesis of 4-aryl/heteroaryl-4H-fused pyrans as anti-proliferative agents. All the synthesized molecules were screened against a panel of human carcinoma cell lines. Description: Significant inhibition was exhibited by the compounds against HCT-116 (Colon) and PC-3 (Prostate) cell lines while A-549 (Lung) cell lines, MiaPaCa-2 (Pancreatic) cell lines and HL-60 (Leukemia Cancer) cell lines were almost resistant to the exposure of the test compounds. Compound FP-(v)n displayed noteworthy cytotoxicity towards HCT-116 malignant cells with the IC50 value of 0.67 μM. It induces apoptosis as revealed by several biological endpoints like apoptotic body formation, through DAPI staining, phase contrast microscopy and mitochondrial membrane potential loss. Moreover FP-(v)n is a potent apoptotic inducer confirmed by cell cycle arrest and ROS generation. The cell phase distribution studies indicate an augment from 4.94 % (control sample) to 39.68 % (sample treated with 1.5 μM compound FP-(v)n) in the apoptotic population. Compound FP-(v)n inhibits the tumor growth in Ehrlich ascites carcinoma (EAC), Ehrlich Tumor (ET, solid) and sarcoma-180 (solid) mice models. Additionally, it was established to be non-toxic at maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. Conclusion: The current study provides an insight into anti-cancer potential of FP-(v)n, which might be valuable in the treatment of tumor.

The aberrant proliferation of tumor cells and abundant vasculature in tumor tissues are closely correlated with receptors that are specifically dysregulated in tumor cells. These tumor-associated targets are critical in early diagnosis and therapy selection. Ligands such as antibodies, proteins, polypeptides and polysaccharides that specifically bind to these targets can significantly improve the detection and cure rate when used as tumor imaging probes or anti-tumor agents. Compared to other targeting ligands, peptides have attracted increasingly more attention in tumor diagnostics and therapeutics because of their small sizes, high affinity, stability, ease of modification and low immunogenicity. Several peptide-based imaging probes and therapeutic agents have already been used in clinical trials. This review summarizes some of the tumor-associated targets and their corresponding peptides, as well as the potential of these peptides in cancer treatment.

Background: Cancer is a grave health problem for the world as the global cancer burden rises to 14 million new cases with 8.2 million deaths every year which is expected to rise by 70% in the next 2 decades as reported by the WHO.These steady rises in death demand for rapid developments in anti-cancer agents. Essential oils, being natural and multi-component complex systems have recently attracted a lot of attention in this search for novel anti-cancer agents. Materials and Methods: The pharmaceutical attributes of essential oil components, specifically focusing on their affinity towards COX, 5-LOX, AKT, MDM2, PDK1 and mTOR which defines the phosphatidylinositol-3- kinase (PI3K) pathway, were assessed. 123 compounds present in essential oils of different plants were analyzed for their drug like attributes which were then allowed to dock with PI3K dependent receptors crucial for the development of cancer malignancies. Among them, 21 compounds were filtered possessing high druglikeness with favourable metabolism offered by major cytochromeP450 isoforms. Finally, the best docked compounds with highest binding affinities were employed for building a ligand based pharmacophore. Being inhibitors of P-glycoproteins, these molecules also exhibited good absorption profiles and noncarcinogenic properties. Further from these 21, six compounds were evaluated against A549 lung cancer cells. Results: The pharmacophoric feature obtained can be applied for both designing and screening moieties for active inhibitors of the phosphatidylinositol-3-kinase pathway specifically from essential oil compounds and these final 21 compounds can be further promoted to studies for anti-cancer drug development. Among these, six compounds exhibited promising inhibitory results against A549 lung cancer cells. Furthermore, immunoblotting assay confirmed the efficacy of the compounds for inhibiting mTOR and AKT enzymes which are bandmasters for downstream signaling of thePI3K pathway. Conclusion: Methyl nonanoate, (R)-citronellol, cis-carveol (L-carveol), 3-methyl-Cyclohexanone, 4-carene and thujopsene were finally screened for PI3K targeted anti-cancer therapies which may find direct application as inhalers or sprays against lung cancer as these compounds are highly volatile.

Description: Two new ruthenium(II) complexes containing guanidinium as ligands, [Ru(dip)2 (L1)]3+ (Ru1) and [Ru(dip)2(L2)]3+ (Ru2) (dip=4,7-diphenyl-1,10-phenanthroline; L1=1-(4-(1H-imidazo[4,5- f][1,10]phenanthrolin-2-yl)phenyl)guanidine cation; L2 = 1-(3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl) phenyl)guanidine cation) have been synthesized and characterized. Both complexes display higher cytotoxicity against several cancer cell lines compared to cisplatin and are less cytotoxic on the nontumorigenic cell line LO2. Intracellular distribution studies show that these complexes are selectively localized in the cytoplasm. Findings: Further analysis revealed that Ru1 and Ru2 had no obvious effects on the cell cycle and induced apoptosis in HeLa cells via the mitochondrial pathway, which involved reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and Bcl-2 family member activation. Taken together, the two complexes have the potential to be utilized as anticancer agents.

Background: 1,3,4-Oxadiazole heterocycles possess a broad spectrum of biological activities. They were reported as potent cytotoxic agents and tubulin inhibitors; hence it is of great interest to explore new oxadiazoles as cytotoxic agents targeting tubulin polymerization. Objective: Two new series of oxadiazoles (5a-h and 12a-h) were synthesized, structurally related to the heterocyclic linked aryl core of IMC-038525, NSC 776715, and NSC 776716, with further modification by incorporating methylene linker. Method: The 2,5-disubstituted-1,3,4-oxadiazoles (5a-h and 12a-h) were synthesized by refluxing an equimolar mixture of the intermediates [(4) and (8a-d)] and aromatic aldehydes in water-ethanol system using sodium bisulphite catalyst. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI US) Protocol, while the tubulin polymerization assay kits from Cytoskeleton ™(bk011p) was used to perform an in vitro tubulin polymerization assay. Results: 2-(5-{[(4-Chlorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)phenol (5f) and 2-[(2,4-dichlorophenoxy) methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole (12c) showed maximum cytotoxicity with the mean percent growth inhibitions (GIs) of 71.56 and 72.68 respectively at 10 μM drug concentrations. Both the compounds (5f and 12c) showed superior cytotoxicity than clinically prevalent anticancer drugs, Imatinib and Gefitinib in one dose assay. The compound 12c showed promising results in five dose assay, with GI50 values varies between 1.61 and >100 μM. Furthermore, the compounds, 5f and 12c also inhibited the polymerization of tubulin with, an IC50 of 2.8 and 2.2 μM, respectively. Conclusion: The oxadiazoles reported herein are tubulin inhibitors and cytotoxic agents. These findings will be helpful in future drug design of more potent tubulin inhibitor cytotoxic agents.

Background and Objective: Multiple drug resistance (MDR) to chemotherapeutic agents often leads to a failure to respond to chemotherapy. We utilized an in vitro chemosensitivity test to identify sensitive and effective chemotherapeutic drugs and further elucidated the correlation between the in vivo chemosensitivity and clinical outcomes. Methods: Here, we evaluated the in vitro chemosensitivity and MDR of 120 lung cancer patients to eight singledrug chemotherapies and of 291 lung cancer patients to seven chemotherapy regimens using an ATP-based tumor chemosensitivity assay (ATP-TCA). Additionally, the chemosensitivity profiles of lung adenocarcinoma patients (284 cases) and lung squamous cell carcinoma patients (90 cases) to these single-drug and chemotherapy regimens were compared. Furthermore, the correlations between the chemosensitivity and clinical outcomes were investigated in 16 stage III squamous cell carcinoma patients. Results and Conclusion: PTX (51.7%), TXT (43.3%), GEM (12.5%), PTX+DDP (62.5%), TXT+L-OHP (54.3%) and VP-16+DDP (16.2%) had the highest in vitro chemosensitivity rates. Approximately 31.7% of patients developed resistance to all eight single-drug chemotherapies, and 25.8% of patients displayed resistance to all seven chemotherapy regimens. In addition, lung squamous cell carcinoma was significantly more sensitive to GEM and MTA+DDP than lung adenocarcinoma (P<0.05). Further analysis showed that patients with higher drug sensitivity tended to have longer disease-free survival (18 months vs. 8.5 months) than patients displaying drug resistance (P<0.05). These results suggest that the implementation of in vitro drug susceptibility testing before chemotherapy can effectively prevent the occurrence of primary drug resistance and inappropriate drug treatment.

Objective: Monoclonal antibodies (mAbs) have been radiolabeled with a variety of radioisotopes utilizing various kinds of bi-functional chelating agents (BFCAs) with an aim to develop suitable agents for radioimmunotherapy. The number of BFCA moieties present per antibody molecule plays a significant role in determining the pharmacokinetics and immunoreactivity exhibited by the radiolabeled antibodies. The objective of the present study is to evaluate the effect of the number of BFCA moieties present per antibody molecule on the pharmacokinetics and immunoreactivity of the 177Lu-labeled Rituximab. Methods: Three different mAb-BFCA conjugates were prepared using different molar ratios of Rituximab (mAb) to p-NCS-benzyl-DOTA (BFCA) viz. 1:5, 1:10 and 1:50 employing different reaction conditions. Studies were carried out to determine the average number of BFCAs attached per mAb molecule. All the three mAb-BFCA conjugates were labeled with 177Lu(III) and were subsequently evaluated in normal Swiss mice to ascertain their respective pharmacokinetic behavior. In-vitro studies were also performed in Raji cell lines (human burkitt's lymphoma) for determining the effect of increasing number of BFCAs attached per mAb molecule on the immunoreactivity of the resultant 177Lu-labeled mAb-BFCA complexes. Results: 177Lu-labeled mAb-BFCA complex prepared corresponding to 1:50 mAb to BFCA ratio exhibited the least non-specific uptake and rapid clearance from majority of the organs, but also exhibited least immunoreactive fraction (IRF = 19.37%). On the other hand, 177Lu-labeled mAb-BFCA complex prepared corresponding to 1:5 mAb to BFCA ratio exhibited the highest non-specific uptake and slower clearance pattern, but highest IRF (71.17%). 177Lu-labeled mAb-BFCA complex prepared corresponding to 1:10 mAb:BFCA ratio exhibited intermediate pharmacokinetic behaviour with moderate IRF (53.05%). Conclusions: The present study indicates that antibody to BFCA ratio plays a crucial role in determining the immunoreactivity and pharmacokinetic behavior of the radiolabeled antibodies and must be prudently chosen for their successful therapeutic application.