Synthesis and Biological Evaluation of Analogs of Didehydroepiandrosterone as Potential New Anticancer Agents

Two benzimidazole derivatives namely 2-methyl-1H-benzimidazole (1) and 1H-benzimidazol-2- ylmethanol (2) were synthesized in high yields by condensing O-phenylenediamine with two different carboxylic acid derivatives: glacial acetic acid and glycolic acid, following a different synthetic protocol. Structures were elucidated by spectroscopic methods. Among the two benzimidazole derivatives synthesized, 2-methyl-1Hbenzimidazole (1) showed moderate antioxidant activity with IC50 values of 144.84?g/ml whereas 1H-benzimidazol- 2-ylmethanol (2) displayed mild antioxidant activity (IC50 value 400.42 ?g/ml). Compound 1 also exhibited prominent cytotoxic activities with the LC50 value of 0.42 ?g/ml when compared to the standard vincristine sulphate (LC50 value of 0.544 ?g/ ml). It also demonstrated weak antimicrobial activity having 7-8 mm of zone of inhibition.Dhaka Univ. J. Pharm. Sci. 15(1): 83-87, 2016 (June)

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QSAR Model of Indeno[1,2-b]indole Derivatives and Identification of N-isopentyl-2-methyl-4,9-dioxo-4,9-Dihydronaphtho[2,3-b]furan-3-carboxamide as a Potent CK2 Inhibitor

Molecules ◽

10.3390/molecules25010097 ◽

2019 ◽

Vol 25 (1) ◽

pp. 97 ◽

Cited By ~ 1

Author(s):

Samer Haidar ◽

Christelle Marminon ◽

Dagmar Aichele ◽

Abdelhamid Nacereddine ◽

Wael Zeinyeh ◽

...

Keyword(s):

Molecular Modeling ◽

Qsar Model ◽

Biological Evaluation ◽

Indole Derivatives ◽

Ic50 Value ◽

Ic50 Values ◽

Synthesis And Biological Evaluation ◽

Ck2 Inhibitors ◽

Ck2 Inhibitor

Casein kinase II (CK2) is an intensively studied enzyme, involved in different diseases, cancer in particular. Different scaffolds were used to develop inhibitors of this enzyme. Here, we report on the synthesis and biological evaluation of twenty phenolic, ketonic, and para-quinonic indeno[1,2-b]indole derivatives as CK2 inhibitors. The most active compounds were 5-isopropyl-1-methyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4h and 1,3-dibromo-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4w with identical IC50 values of 0.11 µM. Furthermore, the development of a QSAR model based on the structure of indeno[1,2-b]indoles was performed. This model was used to predict the activity of 25 compounds with naphtho[2,3-b]furan-4,9-dione derivatives, which were previously predicted as CK2 inhibitors via a molecular modeling approach. The activities of four naphtho[2,3-b]furan-4,9-dione derivatives were determined in vitro and one of them (N-isopentyl-2-methyl-4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-3-carboxamide) turned out to inhibit CK2 with an IC50 value of 2.33 µM. All four candidates were able to reduce the cell viability by more than 60% after 24 h of incubation using 10 µM.

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Design, Synthesis and Biological Evaluation of Novel Osimertinib-Based HDAC and EGFR Dual Inhibitors

Molecules ◽

10.3390/molecules24132407 ◽

2019 ◽

Vol 24 (13) ◽

pp. 2407 ◽

Cited By ~ 6

Author(s):

Hang Dong ◽

Hao Yin ◽

Chunlong Zhao ◽

Jiangying Cao ◽

Wenfang Xu ◽

...

Keyword(s):

Anticancer Agents ◽

Histone Deacetylases ◽

Growth Factor Receptor ◽

Biological Evaluation ◽

Design Synthesis ◽

Lysine Specific Demethylase ◽

Ic50 Values ◽

Dual Inhibitors ◽

Epidermal Growth ◽

Synthesis And Biological Evaluation

Herein a novel series of histone deacetylases (HDACs) and epidermal growth factor receptor (EGFR) dual inhibitors were designed and synthesized based on the structure of the approved EGFR inhibitor osimertinib (AZD9291). Among them, four compounds 5D, 5E, 9D and 9E exhibited more potent total HDAC inhibition than the approved HDAC inhibitor SAHA. However, these compounds only showed moderate to low inhibitory potency towards EGFR with compounds 5E and 9E possessing IC50 values against EGFRWT and EGFRT790M in the micromolar range. 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay revealed the potent antiproliferative activities of compounds 5D, 5E, 9D and 9E, among which 9E was even more potent against HeLa, MDA-MB-231, MDA-MB-468, HT-29 and KG-1 cell lines than SAHA and AZD9291. Further selectivity profile of 9E showed that this compound was not active against other 13 cancer-related kinases and two epigenetic targets lysine specific demethylase 1 (LSD1) and bromodomain-containing protein 4 (BRD4). These results support further structural modification of 9E to improve its EGFR inhibitory activity, which will lead to more potent and balanced HDAC and EGFR dual inhibitors as anticancer agents.

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Convergent synthesis and biological evaluation of vitamin D analogues as potential anticancer agents

10.7287/peerj.preprints.1653 ◽

2016 ◽

Author(s):

Andrzej Kutner

Keyword(s):

Colon Cancer ◽

Vitamin D ◽

Vitamin D Receptor ◽

Anticancer Agents ◽

Biological Evaluation ◽

Side Chain ◽

Synthesis And Biological Evaluation ◽

Ht 29

Synthetic analogs of 1alpha,25-dihydroxycholecalciferol [1alpha,25-(OH)2D3] and 1alpha,25-dihydroxyergocalciferol [1alpha,25-(OH)2D2] have long been considered as key regulators of calcium and phosphate homeostasis. These analogs have been recently investigated as potential therapeutics against a number of pathological states, including metabolic, dermatological, immune and hyperproliferative diseases. Analogues of 1alpha,25-(OH)2D3 and 1alpha,25-(OH)2D2, modified in the cyclohexane A-ring and in the aliphatic side-chain, potentiated the efficiency of cytostatics and/or cooperated efficiently with polyphenol in human myeloid leukemia cells (HL60, U937 and MOLM-13) and in several animal models of leukemias and solid tumours. The therapeutic effect resulted from the thorough combination of several key factors, including the selection of vitamin D-sensitive cancer model, type of cytostatic, the right scheme and route of administration of both therapeutics, correlation with vitamin D receptor level and managing of the hypercalcemic side effect of vitamin D. In this work our synthesis and biological evaluation is outlined of a novel generation of vitamin D analogs as well as our investigation of their anticancer profile in vitro and in vivo. Our convergent synthesis started from vitamin D-like advanced intermediates and separately prepared side-chain fragments. This way, in an over twenty-step syntheses, a series of analogs were obtained containing, compared to the parent vitamin D hormones, 1alpha,25-(OH)2D3 and 1alpha,25-(OH)2D2, an additional chiral center or conjugated diene system in the side-chain and/or modified 5,6-trans or 19-nor A-ring. Some of the new analogs, pre-selected in a number of in vitro models, showed, in the combined treatment with cytostatics, the beneficial activity profile in both, murine colon cancer MC38 and in human colon cancer HT-29 cells. Our analogues also modulated expression of genes related to stem-like phenotype in vitamin D receptor (VDR) positive colon cancer cells, HT-29 and HCT-116, at different differentiation states, undergoing renewal after the treatment with 5-FU. The analogs induced differentiation of VDR positive A375 and VDR negative SK-MEL 188b human melanoma cells. Some of our analogs also displayed moderate cytotoxic and pro-apoptotic activity in diffuse large B-cell lymphoma (DLBCL) and concentration and time-dependent antiproliferative action upon stimulated B-cells from healthy donors. Data available from the protein data bank were used for the rational design of the next generation of analogs by minimizing the electrostatic interaction energies, after the reconstruction of a charge densities using pseudoatom databank. Due to a low calcemic activity and anticancer profile in vivo, selected new analogues might be considered as promising candidates for further preclinical evaluation as potential anticancer agents.

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Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors

Molecules ◽

10.3390/molecules25225371 ◽

2020 ◽

Vol 25 (22) ◽

pp. 5371

Author(s):

Muhammed Çeçen ◽

Jong Min Oh ◽

Zeynep Özdemir ◽

Saliha Ebru Büyüktuncel ◽

Mehtap Uysal ◽

...

Keyword(s):

Biological Evaluation ◽

Inhibitory Potency ◽

Design Synthesis ◽

Docking Simulations ◽

Mao B ◽

Ic50 Value ◽

Competitive Inhibitors ◽

Mao A ◽

Ic50 Values ◽

Synthesis And Biological Evaluation

Twelve pyridazinones (T1–T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC50 value of 0.013 µM, followed by T3 (IC50 = 0.039 µM). Inhibitory potency for MAO-B was more enhanced by meta bromo substitution (T6) than by para bromo substitution (T7). For para substitution, inhibitory potencies for MAO-B were as follows: -Cl (T3) > -N(CH3)2 (T12) > -OCH3 (T9) > Br (T7) > F (T5) > -CH3 (T11) > -H (T1). T6 and T3 efficiently inhibited MAO-A with IC50 values of 1.57 and 4.19 µM and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). T3 and T6 were found to be reversible and competitive inhibitors of MAO-B with Ki values of 0.014 and 0.0071, respectively. Moreover, T6 was less toxic to healthy fibroblast cells (L929) than T3. Molecular docking simulations with MAO binding sites returned higher docking scores for T6 and T3 with MAO-B than with MAO-A. These results suggest that T3 and T6 are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer’s disease.

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Design, synthesis and biological evaluation of novel 5α, 8α-endoperoxide steroidal derivatives with hybrid side chain as anticancer agents

Steroids ◽

10.1016/j.steroids.2019.108471 ◽

2020 ◽

Vol 153 ◽

pp. 108471 ◽

Cited By ~ 1

Author(s):

Hongling Li ◽

Haijun Wang ◽

Jing Wang ◽

Yu Lin ◽

Yukun Ma ◽

...

Keyword(s):

Anticancer Agents ◽

Biological Evaluation ◽

Side Chain ◽

Design Synthesis ◽

Synthesis And Biological Evaluation ◽

Steroidal Derivatives

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Structural Basis of 2-Phenylamino-4-phenoxyquinoline Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Molecules ◽

10.3390/molecules27020461 ◽

2022 ◽

Vol 27 (2) ◽

pp. 461

Author(s):

Arthit Makarasen ◽

Suwicha Patnin ◽

Pongsit Vijitphan ◽

Nanthawan Reukngam ◽

Panita Khlaychan ◽

...

Keyword(s):

Anticancer Agents ◽

Lymphoblastic Leukemia ◽

Biological Evaluation ◽

Structural Basis ◽

Ic50 Values ◽

Target Molecules ◽

Rt Inhibitors ◽

Near Future ◽

Synthesis And Biological Evaluation ◽

Hiv 1

New target molecules, namely, 2-phenylamino-4-phenoxyquinoline derivatives, were designed using a molecular hybridization approach, which was accomplished by fusing the pharmacophore structures of three currently available drugs: nevirapine, efavirenz, and rilpivirine. The discovery of disubstituted quinoline indicated that the pyridinylamino substituent at the 2-position of quinoline plays an important role in its inhibitory activity against HIV-1 RT. The highly potent HIV-1 RT inhibitors, namely, 4-(2′,6′-dimethyl-4′-formylphenoxy)-2-(5″-cyanopyridin-2″ylamino)quinoline (6b) and 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(5″-cyanopyridin-2″ylamino)quinoline (6d) exhibited half-maximal inhibitory concentrations (IC50) of 1.93 and 1.22 µM, respectively, which are similar to that of nevirapine (IC50 = 1.05 µM). The molecular docking results for these two compounds showed that both compounds interacted with Lys101, His235, and Pro236 residues through hydrogen bonding and interacted with Tyr188, Trp229, and Tyr318 residues through π–π stacking in HIV-1 RT. Interestingly, 6b was highly cytotoxic against MOLT-3 (acute lymphoblastic leukemia), HeLA (cervical carcinoma), and HL-60 (promyeloblast) cells with IC50 values of 12.7 ± 1.1, 25.7 ± 0.8, and 20.5 ± 2.1 µM, respectively. However, 6b and 6d had very low and no cytotoxicity, respectively, to-ward normal embryonic lung (MRC-5) cells. Therefore, the synthesis and biological evaluation of 2-phenylamino-4-phenoxyquinoline derivatives can serve as an excellent basis for the development of highly effective anti-HIV-1 and anticancer agents in the near future.

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Convergent synthesis and biological evaluation of vitamin D analogues as potential anticancer agents

10.7287/peerj.preprints.1653v1 ◽

2016 ◽

Author(s):

Andrzej Kutner

Keyword(s):

Colon Cancer ◽

Vitamin D ◽

Vitamin D Receptor ◽

Anticancer Agents ◽

Biological Evaluation ◽

Side Chain ◽

Synthesis And Biological Evaluation ◽

Ht 29

Synthetic analogs of 1alpha,25-dihydroxycholecalciferol [1alpha,25-(OH)2D3] and 1alpha,25-dihydroxyergocalciferol [1alpha,25-(OH)2D2] have long been considered as key regulators of calcium and phosphate homeostasis. These analogs have been recently investigated as potential therapeutics against a number of pathological states, including metabolic, dermatological, immune and hyperproliferative diseases. Analogues of 1alpha,25-(OH)2D3 and 1alpha,25-(OH)2D2, modified in the cyclohexane A-ring and in the aliphatic side-chain, potentiated the efficiency of cytostatics and/or cooperated efficiently with polyphenol in human myeloid leukemia cells (HL60, U937 and MOLM-13) and in several animal models of leukemias and solid tumours. The therapeutic effect resulted from the thorough combination of several key factors, including the selection of vitamin D-sensitive cancer model, type of cytostatic, the right scheme and route of administration of both therapeutics, correlation with vitamin D receptor level and managing of the hypercalcemic side effect of vitamin D. In this work our synthesis and biological evaluation is outlined of a novel generation of vitamin D analogs as well as our investigation of their anticancer profile in vitro and in vivo. Our convergent synthesis started from vitamin D-like advanced intermediates and separately prepared side-chain fragments. This way, in an over twenty-step syntheses, a series of analogs were obtained containing, compared to the parent vitamin D hormones, 1alpha,25-(OH)2D3 and 1alpha,25-(OH)2D2, an additional chiral center or conjugated diene system in the side-chain and/or modified 5,6-trans or 19-nor A-ring. Some of the new analogs, pre-selected in a number of in vitro models, showed, in the combined treatment with cytostatics, the beneficial activity profile in both, murine colon cancer MC38 and in human colon cancer HT-29 cells. Our analogues also modulated expression of genes related to stem-like phenotype in vitamin D receptor (VDR) positive colon cancer cells, HT-29 and HCT-116, at different differentiation states, undergoing renewal after the treatment with 5-FU. The analogs induced differentiation of VDR positive A375 and VDR negative SK-MEL 188b human melanoma cells. Some of our analogs also displayed moderate cytotoxic and pro-apoptotic activity in diffuse large B-cell lymphoma (DLBCL) and concentration and time-dependent antiproliferative action upon stimulated B-cells from healthy donors. Data available from the protein data bank were used for the rational design of the next generation of analogs by minimizing the electrostatic interaction energies, after the reconstruction of a charge densities using pseudoatom databank. Due to a low calcemic activity and anticancer profile in vivo, selected new analogues might be considered as promising candidates for further preclinical evaluation as potential anticancer agents.

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