Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents

Phenanthroindolizidines, such as antofine and tylophorine, are a family of natural alkaloids isolated from different species of Asclepiadaceas. They are characterized by interesting biological activities, such as pronounced cytotoxicity against different human cancerous cell lines, including multidrug-resistant examples. Nonetheless, these derivatives are associated with severe neurotoxicity and loss of in vivo activity due to the highly lipophilic nature of the alkaloids. Here, we describe the development of highly polar prodrugs of antofine and tylophorine as hypoxia-targeted prodrugs. The developed quaternary ammonium salts of phenanthroindolizidines showed high chemical and metabolic stability and are predicted to have no penetration through the blood–brain barrier. The designed prodrugs displayed decreased cytotoxicity when tested under normoxic conditions. However, their cytotoxic activity considerably increased when tested under hypoxic conditions.

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Design, Synthesis, and Biological Evaluation of Novel N-Acylhydrazone Bond Linked Heterobivalent β-Carbolines as Potential Anticancer Agents

Molecules ◽

10.3390/molecules24162950 ◽

2019 ◽

Vol 24 (16) ◽

pp. 2950 ◽

Cited By ~ 3

Author(s):

Chen ◽

Guo ◽

Ma ◽

Chen ◽

Fan ◽

...

Keyword(s):

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Chorioallantoic Membrane ◽

Cancer Cell Lines ◽

Biological Evaluation ◽

In Vivo Model ◽

Ic50 Values

Utilizing a pharmacophore hybridization approach, we have designed and synthesized a novel series of 28 new heterobivalent β-carbolines. The in vitro cytotoxic potential of each compound was evaluated against the five cancer cell lines (LLC, BGC-823, CT-26, Bel-7402, and MCF-7) of different origin—murine and human, with the aim of determining the potency and selectivity of the compounds. Compound 8z showed antitumor activities with half-maximal inhibitory concentration (IC50) values of 9.9 ± 0.9, 8.6 ± 1.4, 6.2 ± 2.5, 9.9 ± 0.5, and 5.7 ± 1.2 µM against the tested five cancer cell lines. Moreover, the effect of compound 8z on the angiogenesis process was investigated using a chicken chorioallantoic membrane (CAM) in vivo model. At a concentration of 5 μM, compound 8z showed a positive effect on angiogenesis. The results of this study contribute to the further elucidation of the biological regulatory role of heterobivalent β-carbolines and provide helpful information on the development of vascular targeting antitumor drugs.

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Synthesis and biological evaluation of thiophene-based hydroxamate derivatives as HDACis with antitumor activities

Future Medicinal Chemistry ◽

10.4155/fmc-2019-0343 ◽

2020 ◽

Vol 12 (8) ◽

pp. 655-672 ◽

Cited By ~ 1

Author(s):

Feifei Yang ◽

Lina Han ◽

Na Zhao ◽

Yang Yang ◽

Di Ge ◽

...

Keyword(s):

Anticancer Agents ◽

Histone Deacetylases ◽

Hdac Inhibitors ◽

Xenograft Model ◽

Biological Evaluation ◽

Anticancer Activities ◽

Antitumor Activities ◽

Cancer Treatments

Aim: Histone deacetylases (HDACs) are one of the validated targets for cancer treatments. In our previous work, we designed a series of bis-substituted aromatic amide HDAC inhibitors (HDACis), among which compounds 7 and 8 showed promising anticancer effects. However, the low solubilities prevented their subsequent developments. We developed additional thiophene-based hydroxamate HDACis in order to improve their physicochemical properties. Materials & methods: In vitro biological evaluations of these analogs revealed potent antiproliferative and antimigrated activities. More importantly, compound 10h exhibited excellent in vivo antitumor activities in MDA-MB-231 xenograft model mice. Furthermore, 10h showed better anticancer activities and drug-like properties than 7. Results & conclusion: Our results proved that thiophene-based hydroxamate HDACis can serve as a promising framework for developing potential 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 novel benzodiazepine derivatives as anticancer agents through inhibition of tubulin polymerization in vitro and in vivo

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2019.111670 ◽

2019 ◽

Vol 182 ◽

pp. 111670 ◽

Cited By ~ 2

Author(s):

Yanqing Pang ◽

Haibiao Lin ◽

Caiwen Ou ◽

Yingying Cao ◽

Baijiao An ◽

...

Keyword(s):

Anticancer Agents ◽

Biological Evaluation ◽

Tubulin Polymerization ◽

Design Synthesis ◽

Benzodiazepine Derivatives ◽

Synthesis And Biological Evaluation

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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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Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value

Current Drug Targets ◽

10.2174/1389450120666190429120314 ◽

2019 ◽

Vol 20 (12) ◽

pp. 1227-1243

Author(s):

Hina Qamar ◽

Sumbul Rehman ◽

D.K. Chauhan

Keyword(s):

Side Effects ◽

Medicinal Plants ◽

Anticancer Agents ◽

Drug Targets ◽

Psidium Guajava ◽

Current Status ◽

Future Perspective ◽

Wide Range

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

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Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892815666200131120618 ◽

2020 ◽

Vol 15 (1) ◽

pp. 2-13 ◽

Cited By ~ 3

Author(s):

Hongyu Tao ◽

Ling Zuo ◽

Huanli Xu ◽

Cong Li ◽

Gan Qiao ◽

...

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

Kinase Inhibitors ◽

Protein Kinase Inhibitors ◽

Cdk Inhibitors ◽

Comprehensive Overview ◽

P53 Expression ◽

Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

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Zingiber zerumbet(L.) Smith: A Review of Its Ethnomedicinal, Chemical, and Pharmacological Uses

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2011/543216 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 80

Author(s):

N. J. Yob ◽

S. Mohd. Jofrry ◽

M. M. R. Meor. Mohd. Affandi ◽

L. K. Teh ◽

M. Z. Salleh ◽

...

Keyword(s):

Medicinal Plant ◽

Traditional Medicine ◽

Biological Evaluation ◽

Perennial Herb ◽

Zingiber Zerumbet ◽

Tropical Countries ◽

Traditional Uses ◽

Worm Infestation

Zingiber zerumbetSm., locally known to the Malay as “Lempoyang,” is a perennial herb found in many tropical countries, including Malaysia. The rhizomes ofZ. zerumbet, particularly, have been regularly used as food flavouring and appetizer in various Malays' cuisines while the rhizomes extracts have been used in Malay traditional medicine to treat various types of ailments (e.g., inflammatory- and pain-mediated diseases, worm infestation and diarrhea). Research carried out using differentin vitroandin vivoassays of biological evaluation support most of these claims. The active pharmacological component ofZ. zerumbetrhizomes most widely studied is zerumbone. This paper presents the botany, traditional uses, chemistry, and pharmacology of this medicinal plant.

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