Effect of substitution at N″-position of N′-hydroxy-N-amino guanidines on tumor cell growth (original) (raw)
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Current Physical Chemistry, 2014
Heterogeneous ribonucleoprotein K (hnRNP K) is a constitutive protein found in nucleus, cytoplasm and mitochondria of cells and interacts with diverse molecules involved in gene expression and signal transduction. Its over expression is associated with the development of prostate, breast and colorectal cancer types. The binding to nucleotides is the main interaction that triggers biological activity and is mediated by its three K homology (KH) domains. Trying to optimize a benzimidazole and a phenylbenzamide derivatives, already reported as hnRNP K ligands, and generate novel ligand candidates with potential anticancer activity, bioisosteric replacements were suggested in the molecular groups able to perform polar interactions with R40 and R59, the main residues of KH3 domain responsible for nucleotide recognition. The top-ranked fragments from BROOD database regarding interaction with the protein, and also steric and electrostatic similarity with query fragments, were selected as potential bioisosters. The novel fragments when inserted in the benzimidazole and phenyilbenzamide derivatives could interact with R40 or R59 by hydrogen bond or ionic interaction. Some of the selected fragments show toxicophoric groups able to induce hepatotoxicity, carcinogenicity and chromosome damage. In this way, the bioisosters without classical toxicophoric groups should be prioritized for synthesis of novel lead compounds, generating diversity in the continuous search of effective and safer anticancer drugs.
Anti-Cancer Agents in Medicinal Chemistry
Bentham sciences, 2022
Cancer has emerged as one of the leading causes of death globally, partly due to the steady rise in anticancer drug resistance. Pyrimidine and pyrimidine-fused heterocycles are some of the privileged scaffolds in medicine, as they possess diverse biological properties. Pyrimidines containing azole nucleus possess inestimable anticancer potency and can potentially regulate cellular pathways for selective anticancer activity. The present review outlines the molecular structure of pyrimidine-fused azoles with significant anticancer activity. The structure activity relationship and molecular docking studies have also been discussed. The current review is the first complete compilation of significant literature on the proposed topic from 2016 to 2020. The information contained in this review offers a useful insight to chemists in the design of new and potent anticancer azole-pyrimidine analogues.
European journal of medicinal chemistry, 2017
A series of new 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives have been synthesized and evaluated in vitro by MTT assays for their antiproliferative activity against cell lines of colon cancer HCT-116, cervical cancer HeLa and breast cancer MCF-7. The obtained results indicated that these compounds display prominent cytotoxic effect. The best anticancer properties have been observed for derivatives 44 (IC50 = 6-18 μM) and 45 (IC50 = 8-14 μM). Very good results of antiproliferative assays have been also shown for compounds 26, 36, and 46 and noticeable anticancer profile has been found for set of derivatives 34-39. Based on results of MTT assays the structure-activity relationships have been drawn. More in-depth biological research revealed that compounds 26, 33, 37, 39, 41 and 43 display cytotoxic effect only against cancer cells and do not inhibit the growth of non-malignant HaCaT cells. Furthermore, the novel series of derivatives have shown g...
Journal of Molecular Graphics & Modelling, 2018
This paper deals with in silico evaluation of newly proposed heterocyclic derivatives in search of potential anticancer activity. Best possible drug candidates have been proposed using a rational approach employing a pipeline of computational techniques namely MetaPrint2D prediction, molinspiration, cheminformatics, Osiris Data warrior, AutoDock and iGEMDOCK. Lazar toxicity prediction, AdmetSAR predictions, and targeted docking studies were also performed. 27 heterocyclic derivatives were selected for bioactivity prediction and drug likeness score on the basis of Lipinski's rule, Viber rule, Ghose filter, leadlikeness and Pan Assay Interference Compounds (PAINS) rule. Bufuralol, Sunitinib, and Doxorubicin were selected as reference standard drug for the comparison of molecular descriptors and docking. Bufuralol is a known non-selective adreno-receptor blocking agent. Studies showed that beta blockers are also used against different types of cancers. Sunitinib is well known Food and Drug administration (FDA) approved pyrrole containing tyrosine kinase inhibitor and our proposed molecules possess similarities with both drug and doxorubicin is another moiety having anticancer activity. All heterocyclic derivatives were found to obey the drug filters except standard drug Doxorubicin. Bioactivity score of the compounds was predicted for drug targets including enzymes, nuclear receptors, kinase inhibitors, G protein-coupled receptor (GPCR) ligands and ion channel modulators. Absorption, distribution, metabolism and toxicity (ADMET) prediction of all proposed compound showed good Blood-brain barrier (BBB) penetration, Human intestinal absorption (HIA), Caco-2 cell permeability except compound-11 and was found to have no AdmetSAR toxicity as well as carcinogenic effect. Compounds 1-9 were slightly mutagenic while compound 2, 11, 20 and 21 showed carcinogenic effect according to Lazar toxicity prediction. Rests of the compounds were predicted to have no side effect. Molecular docking was performed with vascular endothelial growth factor receptor-2(VEGFR2) and glutathione Stransferase-1(GSTP1) because both are common cancer causing proteins. Sunitinib and Doxorubicin possess great affinity to inhibit these cancers causing protein. Self-organizing map (SOM) was used to depict data in a simple 2D presentation. Our studies justify that good oral bioavailability and therapeutic efficacy of 10, 12-19 and 22-27 compounds can be considered as potential anticancer agents.
Guanylation Reactions for the Rational Design of Cancer Therapeutic Agents
International Journal of Molecular Sciences
The modular synthesis of the guanidine core by guanylation reactions using commercially available ZnEt2 as a catalyst has been exploited as a tool for the rapid development of antitumoral guanidine candidates. Therefore, a series of phenyl-guanidines were straightforwardly obtained in very high yields. From the in vitro assessment of the antitumoral activity of such structurally diverse guanidines, the guanidine termed ACB3 has been identified as the lead compound of the series. Several biological assays, an estimation of AMDE values, and an uptake study using Fluorescence Lifetime Imaging Microscopy were conducted to gain insight into the mechanism of action. Cell death apoptosis, induction of cell cycle arrest, and reduction in cell adhesion and colony formation have been demonstrated for the lead compound in the series. In this work, and as a proof of concept, we discuss the potential of the catalytic guanylation reactions for high-throughput testing and the rational design of gu...
Indian Journal of Pharmaceutical Sciences, 2018
Chemotherapy is often the treatment of choice for many types of cancer and the search for new chemotherapeutic agents still plays a major role in the fight against cancer. A reasonable approach in this area deals with use of compounds interacting with DNA and/or inhibiting enzymes critical for cell survival and replication. Amsacrine is one such compound, a well-known antiproliferative agent used to treat some types of cancers including acute adult leukaemia [1]. The poisoning of topo II activity inhibits the relegation process and causes lethal double-strand breaks in DNA, leading to cell cycle arrest and apoptosis. The intercalative property was referred to the planar aromatic system of the acridine moiety [2]. In the same context, acridines have gained strong ground for various biological activities like antimicrobial [3] , antioxidant [4] , anticancer [5-8] , antimalarial [9] , antiinflammatory [10] , analgesic [11] , antileishmanial [12] , antinociceptive [13] , acetylcholinesterase inhibitory [14] and antiherpes [15]. Amsacrine is the best known compound of 9-anilinoacridines series. It was one of the first DNA-intercalating agents to be considered as a topoisomerase II inhibitor. The intercalation process is the strongest type of reversible binding to the double helical DNA in compounds with sufficiently large coplanar aromatic chromophore. Several detailed SAR studies of acridine-based DNA-intercalating agents suggest that the mode of binding is important and the chromophore intercalate with the DNA base
European Journal of Medicinal Chemistry, 2014
A series of novel N-substituted N 0 -(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines 9 e41 have been synthesized and investigated as inhibitors of four isoforms of zinc enzyme carbonic anhydrase (CA.EC 4.2.1.1), that is the cytosolic CA I and II, and cancer-associated isozymes CA IX and XII. Against the human CA I investigated compounds showed K I in the range of 87e6506 nM, toward hCA II ranging from 7.8 to 4500 nM, against hCA IX in the range of 4.7e416 nM and against hCA XII at range of 0.96e540 nM. Compounds 10, 12e14, 16, 18e20, 24e26, 31 and 32 exhibited a powerful inhibitory potency toward hCA IX (K I ¼ 4.7e21 nM) in comparison to the reference sulfonamides AAZ, MZA, EZA, DCP and IND (K I ¼ 24e50 nM). Compound 14 was the most potent inhibitor of hCA I (K I ¼ 87 nM), hCA IX (K I ¼ 4.7 nM) and hCA XII (K I ¼ 0.96 nM), while 26 was the most effective inhibitor of hCA II (K I ¼ 7.8 nM). The most promising compound 32 exerted the highest selectivity ratios toward hCA IX versus hCA I (hCA I/hCA IX ¼ 261) and hCA II (hCA II/hCA IX ¼ 26). The in vitro antitumor activity of compounds 32, 38 and 41 was evaluated at the US National Cancer Institute (NCI) against a panel of 60 human tumor cell lines. The most active antitumor agents 21 and 25, inhibiting 32e35 human tumor cell lines with GI 50 in the range of 2.1e5.0 mM also showed relatively high inhibitory activity toward hCA IX and XII with K I from 18 to 40 nM.
Benzazolo[3,2-a]quinolium salts (BQS) are cationic quaternary alkaloids with similar structure to the anticancer agent ellipticine. This study describes the synthesis and screen, at the experimental con- centration of 10 mM, utilizing the 60 cell line anti-cancer screening of two BQS, namely, 7-benzyl-3- aminobenzimidazo[3,2-a]quinolinium chloride (ABQ-48: NSC D-763307) and the corresponding 7-benzyl-3-nitrobenzimidazo[3,2-a]quinolinium chloride (NBQ 48: NSC D-763303). Compound ABQ-48: NSC D-763307 was also screened in the 5-dose NCI panel. These compounds differ in the presence of an amino or nitro substituent at the 3-position in ring A. The data show that ABQ 48 with electron donating amino group at position 3 in ring A is highly effec- tive in the growth inhibition in several cancer cell lines. However, its analog NBQ 48 which has an electronwithdrawing nitrogen group at this position has negligible effect in most of the cell lines. In particular, ABQ 48 shows >90% growth inhibition in KM12, U251 & SK-MEL-5; and >70% growth inhibition in several cell lines. As per the NCI’s screening criteria ABQ 48 showed better than 60% growth inhibition in at least eight tumor cell lines, and thus, selected for the five dose response study. It is therefore concluded that the biological activity of these compounds is greatly affected by their electron donating properties. Additionally, this work describes the complete proton and carbon-13 chemical shifts assignments using 1D and 2D nuclear magnetic resonance techniques.