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

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.

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

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.

scholarly journals Synthesis, CYP24A1-Dependent Metabolism and Antiproliferative Potential against Colorectal Cancer Cells of 1,25-Dihydroxyvitamin D2 Derivatives Modified at the Side Chain and the A-Ring

2020 ◽  
Vol 21 (2) ◽  
pp. 642
Author(s):  
Magdalena Milczarek ◽  
Michał Chodyński ◽  
Anita Pietraszek ◽  
Martyna Stachowicz-Suhs ◽  
Kaori Yasuda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Vitamin D ◽  
Cancer Cells ◽  
Biologically Active ◽  
Side Chain ◽  
Anticancer Properties ◽  
Colorectal Cancer Cells ◽  
Ht 29

Experimental data indicate that low-calcemic vitamin D derivatives (VDDs) exhibit anticancer properties, both in vitro and in vivo. In our search for a vitamin D analog as potential anticancer agent, we investigated the influence of chirality in the side chain of the derivatives of 1,25-dihydroxyergocalciferol (1,25D2) on their activities. In this study, we synthesized modified analogs at the side chain and the A-ring, which differed from one another in their absolute configuration at C-24, namely (24S)- and (24R)-1,25-dihydroxy-19-nor-20a-homo-ergocalciferols (PRI-5105 and PRI-5106, respectively), and evaluated their activity. Unexpectedly, despite introducing double-point modifications, both analogs served as very good substrates for the vitamin D-hydroxylating enzyme. Irrespective of their absolute C-24 configuration, PRI-5105 and PRI-5106 showed relatively low resistance to CYP24A1-dependent metabolic deactivation. Additionally, both VDDs revealed a similar antiproliferative activity against HT-29 colorectal cancer cells which was higher than that of 1,25D3, the major biologically active metabolite of vitamin D. Furthermore, PRI-5105 and PRI-5106 significantly enhanced the cell growth-inhibitory activity of 5-fluorouracil on HT-29 cell line. In conclusion, although the two derivatives showed a relatively high anticancer potential, they exhibited undesired high metabolic conversion.

scholarly journals Synthesis and Biological Evaluation of Novel Betulin Derivatives with Aromatic Hydrazone Side Chain as Potential Anticancer Agents

2021 ◽  
Author(s):  
Jiafeng Wang ◽  
Jiale Wu ◽  
Yinglong Han ◽  
Jie Zhang ◽  
Yu Lin ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Antitumor Agents ◽  
Biological Evaluation ◽  
Carcinoma Cells ◽  
Side Chain ◽  
Human Carcinoma ◽  
Hct 116 ◽  
Synthesis And Biological Evaluation ◽  
Mcf 7

A series of novel betulin-28-hydrazone derivatives (7a-7o) were synthesized. All compounds were evaluated for their in vitro cytotoxicities in four human carcinoma cells (HepG2, MCF-7, HCT-116 and A549). Among them, compound 7l displayed the most potent cytotoxicity with an IC50 (concentration of the tested compound that inhibits 50% of cell growth) value of 7.37 ± 0.38 μM against MCF-7 cells. The preliminary cellular mechanism studies indicated that compound 7l could induce MCF-7 cells apoptosis. The above findings indicated that compound 7l may be used as a lead compound for antitumor agents with improved efficacy.

scholarly journals Synthesis and biological evaluation of some novel pyrazolopyrimidines incorporating a benzothiazole ring system

2013 ◽  
Vol 63 (1) ◽  
pp. 19-30 ◽  
Author(s):  
Mohammed Afzal Azam ◽  
Loganathan Dharanya ◽  
Charu Chandrakant Mehta ◽  
Sumit Sachdeva
Keyword(s):  
Antimicrobial Activity ◽  
Diclofenac Sodium ◽  
Biological Evaluation ◽  
Ring System ◽  
Standard Drug ◽  
Anti Inflammatory ◽  
Pyrimidine Moiety ◽  
Synthesis And Biological Evaluation

In the present study, a series of benzothiazol derivatives 3a-l containing pyrazolo[3,4-d]pyrimidine moiety at the second position were synthesized and characterized by analytical and spectral data. The compounds were tested for their in vitro antimicrobial activity. Compounds 1-(1,3-benzothiazol-2- yl)-3-methyl-4-phenyl-1H-pyrazolo[3,4-d]pyrimidine (3a), 1- (1,3-benzothiazol-2-yl)-4-(4-chlorophenyl)-3-methyl-1H-pyrazolo[ 3,4-d]pyrimidine (3d) and 1-(1,3-benzothiazol-2-yl)- 3-methyl-4-substituted phenyl-1H-pyrazolo[3,4-d]pyrimidines (3h-j) showed significant inhibitory activity against P. aeruginosa whereas compounds 1-(1,3-benzothiazol-2-yl)-4- (2-chlorophenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (3b), 2-[1-(1,3-benzothiazol-2-yl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-yl]phenol (3e), 1-(1,3-benzothiazol-2-yl)-4-(3,4-dimethoxyphenyl)- 3-methyl-1H-pyrazolo[3,4-d]pyrimidine (3h), 4-[1-(1,3-benzothiazol-2-yl)-3-methyl-1H-pyrazolo[3,4-d]pyri midin-4-yl]-N,N-dimethylaniline (3j) and 1-(1,3-benzothiazol- 2-yl)-3-methyl-4-[2-phenylvinyl]-1H-pyrazolo[3,4-d]pyrimidine (3k) were found to be active against C. albicans. Some of these synthesized compounds were evaluated for their in vivo acute toxicity, analgesic, anti-inflammatory, and ulcerogenic actions. The tested compound 4-[1-(1,3-benzothiazol- 2-yl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N, N-dimethylaniline (3j) exhibited maximum analgesic and anti-inflammatory activities. Compounds 1-(1,3-benzothiazol- -2-yl)-3-methyl-4-(3-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidine (3i) and 3j showed a significant gastrointestinal protection compared to the standard drug diclofenac sodium.

Synthesis, characterization and in vitro and in vivo anticancer activity of Pt(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)]

2017 ◽  
Vol 46 (21) ◽  
pp. 7005-7019 ◽  
Author(s):  
Benjamin W. J. Harper ◽  
Emanuele Petruzzella ◽  
Roman Sirota ◽  
Fernanda Fabiola Faccioli ◽  
Janice R. Aldrich-Wright ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Biological Evaluation ◽  
Synthesis And Biological Evaluation ◽  
Derivatives Of

Synthesis and biological evaluation in vitro and in vivo of functionalized Pt(iv) derivatives of Pt56MeSS.

scholarly journals Design, Synthesis and Biological Evaluation of Novel 1, 3, 4-Oxadiazole Bearing Pyridine Moiety

2019 ◽  
pp. 300-307
Author(s):  
Asma D. Ambekari ◽  
Shrinivas K. Mohite
Keyword(s):  
Antimicrobial Activity ◽  
Mass Spectra ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Pyridine Moiety ◽  
Anti Inflammatory ◽  
Physicochemical Data ◽  
Synthesis And Biological Evaluation

Series of novel substituted Synthesis of N-{[5-(substituted)-1,3,4-oxadiazole-2-yl] carbamothioyl} derivatives containing 1,3,4-oxadiazole moiety were synthesized by microwave as a green chemistry method and conventional method by using pyridine 3- carboxylic acid as a starting material. The structures of the synthesized compounds were characterized by physicochemical data, IR, Mass spectra and 1HNMR. All the newly synthesized compound screened for their antimicrobial and In-vivo and In-vitro Anti-inflammatory studies. Anti-inflammatory studies revealed that compound 4f showed significant in-vivo and in-vitro anti-inflammatory activity as well potent antimicrobial activity.

Sign in / Sign up

Export Citation Format

Share Document