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

2020 ◽  
Vol 15 (1) ◽  
pp. 2-13 ◽  
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.

scholarly journals Targeting IDH1/2 mutant cancers with combinations of ATR and PARP inhibitors

NAR Cancer ◽  
2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Amrita Sule ◽  
Jinny Van Doorn ◽  
Ranjini K Sundaram ◽  
Sachita Ganesa ◽  
Juan C Vasquez ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Isocitrate Dehydrogenase 1 ◽  
Normal Product ◽  
Synthetic Lethal Interactions ◽  
Mutant Cells

Abstract Mutations in the isocitrate dehydrogenase-1 and -2 (IDH1/2) genes were first identified in glioma and acute myeloid leukemia (AML), and subsequently found in multiple other tumor types. These neomorphic mutations convert the normal product of enzyme, α-ketoglutarate (αKG), to the oncometabolite 2-hydroxyglutarate (2HG). Our group recently demonstrated that 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state referred to as ‘BRCAness’, which confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we sought to elucidate sensitivity of IDH1/2-mutant cells to DNA damage response (DDR) inhibitors and, whether combination therapies could enhance described synthetic lethal interactions. Here, we report that ATR (ataxia telangiectasia and Rad3-related protein kinase) inhibitors are active against IDH1/2-mutant cells, and that this activity is further potentiated in combination with PARP inhibitors. We demonstrate this interaction across multiple cell line models with engineered and endogenous IDH1/2 mutations, with robust anti-tumor activity in vitro and in vivo. Mechanistically, we found ATR and PARP inhibitor treatment induces premature mitotic entry, which is significantly elevated in the setting of IDH1/2-mutations. These data highlight the potential efficacy of targeting HR defects in IDH1/2-mutant cancers and support the development of this combination in future clinical trials.

scholarly journals Application of a PBPK Model of Rivaroxaban to Prospective Simulations of Drug-Drug-Disease Interactions with Protein Kinase Inhibitors in CA-VTE

2021 ◽  
Author(s):  
Eleanor Jing Yi Cheong ◽  
Daniel Zhi Wei Ng ◽  
Sheng Yuan Chin ◽  
Ziteng Wang ◽  
Eric Chun Yong Chan
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Pbpk Model ◽  
Organic Anion ◽  
Protein Kinase Inhibitors ◽  
Organic Anion Transporter ◽  
Pbpk Modelling ◽  
Anion Transporter

Background and Purpose Rivaroxaban is emerging as a viable anticoagulant for the pharmacological management of cancer associated venous thromboembolism (CA-VTE). Being eliminated via CYP3A4/2J2-mediated metabolism and organic anion transporter 3 (OAT3)/P-glycoprotein-mediated renal secretion, rivaroxaban is susceptible to drug-drug interactions (DDIs) with protein kinase inhibitors (PKIs), erlotinib and nilotinib. Physiologically based pharmacokinetic (PBPK) modelling was applied to interrogate the DDIs for dose adjustment of rivaroxaban in CA-VTE. Experimental Approach The inhibitory potencies of erlotinib and nilotinib on CYP3A4/2J2-mediated metabolism of rivaroxaban were characterized. Using prototypical OAT3 inhibitor ketoconazole, in vitro OAT3 inhibition assays were optimized to ascertain the in vivo relevance of derived inhibitory constants (K). DDIs between rivaroxaban and erlotinib or nilotinib were investigated using iteratively verified PBPK model. Key Results Mechanism-based inactivation (MBI) of CYP3A4-mediated rivaroxaban metabolism by both PKIs and MBI of CYP2J2 by erlotinib were established. The importance of substrate specificity and nonspecific binding to derive OAT3-inhibitory K values of ketoconazole and nilotinib for the accurate prediction of DDIs was illustrated. When simulated rivaroxaban exposure variations with concomitant erlotinib and nilotinib therapy were evaluated using published dose-exposure equivalence metrics and bleeding risk analyses, dose reductions from 20 mg to 15 mg and 10 mg in normal and mild renal dysfunction, respectively, were warranted. Conclusion and Implications We established the PBPK-DDI platform to prospectively interrogate and manage clinically relevant interactions between rivaroxaban and PKIs in patients with underlying renal impairment. Rational dose adjustments were proposed, attesting to the capacity of PBPK modelling in facilitating precision medicine.

scholarly journals Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy

2015 ◽  
Vol 113 (1) ◽  
pp. 182-187 ◽  
Author(s):  
Christina H. Eng ◽  
Zuncai Wang ◽  
Diane Tkach ◽  
Lourdes Toral-Barza ◽  
Savuth Ugwonali ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Cell Types ◽  
Loss Of Function ◽  
Growth And Survival ◽  
Oncogenic Mutations ◽  
Cellular Context ◽  
Genetic Stratification

Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. By profiling 47 cell lines with pharmacological and genetic loss-of-function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of autophagy-related 7 (ATG7) by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy.

Abstract 4499: In vitro and in vivo evaluation of novel Pim kinase inhibitors with potent anticancer activity

2010 ◽  
Author(s):  
Krzysztof Brzozka ◽  
Adrian Zarebski ◽  
Ewa Trebacz ◽  
Wojciech Czardybon ◽  
Marek Chołody ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Kinase Inhibitors ◽  
In Vivo Evaluation

Discovery of steroidal lactam conjugates of POPAM-NH2 with potent anticancer activity

2020 ◽  
Vol 12 (1) ◽  
pp. 19-35 ◽  
Author(s):  
Dimitrios Trafalis ◽  
Panagiotis Dalezis ◽  
Elena Geromichalou ◽  
Sofia Sagredou ◽  
Eleni Sflakidou ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Alkylating Agents ◽  
Experimental Models ◽  
The Novel ◽  
Nitrogen Mustards ◽  
Experimental Systems ◽  
High Antitumor Activity

Aim: Steroidal prodrugs of nitrogen mustards such as estramustine and prednimustine have proven effective anticancer agents in clinical use since the 1970s. In this work, we aimed to develop steroidal prodrugs of the novel nitrogen mustard POPAM-NH2. POPAM-NH2 is a melphalan analogue that was coupled with three different steroidal lactams. Methodology: The new conjugates were preclinically tested for anticancer activity against nine human and one rodent cancer experimental models, in vitro and in vivo. Results & conclusion: All the steroidal alkylators showed high antitumor activity, in vitro and in vivo, in the experimental systems tested. Moreover, these hybrid compounds showed by far superior anticancer activity compared with the alkylating agents, melphalan and POPAM-NH2.

scholarly journals Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors.

1996 ◽  
Vol 16 (12) ◽  
pp. 6623-6633 ◽  
Author(s):  
P D Adams ◽  
W R Sellers ◽  
S K Sharma ◽  
A D Wu ◽  
C M Nalin ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Cyclin A ◽  
Cdk Inhibitors ◽  
Cyclin Dependent Kinase ◽  
Binding Motifs ◽  
Recognition Motif ◽  
Binding Inhibition ◽  
In Vivo Growth

Understanding how cyclin-cdk complexes recognize their substrates is a central problem in cell cycle biology. We identified an E2F1-derived eight-residue peptide which blocked the binding of cyclin A and E-cdk2 complexes to E2F1 and p21. Short peptides spanning similar sequences in p107, p130, and p21-like cdk inhibitors likewise bound to cyclin A-cdk2 and cyclin E-cdk2. In addition, these peptides promoted formation of stable cyclin A-cdk2 complexes in vitro but inhibited the phosphorylation of the retinoblastoma protein by cyclin A- but not cyclin B-associated kinases. Mutation of the cyclin-cdk2 binding motifs in p107 and E2F1 likewise prevented their phosphorylation by cyclin A-associated kinases in vitro. The cdk inhibitor p21 was found to contain two functional copies of this recognition motif, as determined by in vitro kinase binding/inhibition assays and in vivo growth suppression assays. Thus, these studies have identified a cyclin A- and E-cdk2 substrate recognition motif. Furthermore, these data suggest that p21-like cdk inhibitors function, at least in part, by blocking the interaction of substrates with cyclin-cdk2 complexes.

Protein kinase inhibitors can control the progression of endometriosis in vitro and in vivo

2010 ◽  
Vol 222 (2) ◽  
pp. 148-157 ◽  
Author(s):  
Charlotte Ngô ◽  
Carole Nicco ◽  
Mahaut Leconte ◽  
Christiane Chéreau ◽  
Sylviane Arkwright ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors

scholarly journals Stem Rust Spores Elicit Rapid RPG1 Phosphorylation

2010 ◽  
Vol 23 (12) ◽  
pp. 1635-1642 ◽  
Author(s):  
Jayaveeramuthu Nirmala ◽  
Tom Drader ◽  
Xianming Chen ◽  
Brian Steffenson ◽  
Andris Kleinhofs
Keyword(s):  
Disease Resistance ◽  
Stem Rust ◽  
Kinase Inhibitors ◽  
Durable Resistance ◽  
Kinase Domain ◽  
Protein Kinase Inhibitors ◽  
Disease Resistance Protein ◽  
Resistance Protein

Stem rust threatens cereal production worldwide. Understanding the mechanism by which durable resistance genes, such as Rpg1, function is critical. We show that the RPG1 protein is phosphorylated within 5 min by exposure to spores from avirulent but not virulent races of stem rust. Transgenic mutants encoding an RPG1 protein with an in vitro inactive kinase domain fail to phosphorylate RPG1 in vivo and are susceptible to stem rust, demonstrating that phosphorylation is a prerequisite for disease resistance. Protein kinase inhibitors prevent RPG1 phosphorylation and result in susceptibility to stem rust, providing further evidence for the importance of phosphorylation in disease resistance. We conclude that phosphorylation of the RPG1 protein by the kinase activity of the pK2 domain induced by the interaction with an unknown pathogen spore product is required for resistance to the avirulent stem rust races. The pseudokinase pK1 domain is required for disease resistance but not phosphorylation. The very rapid phosphorylation of RPG1 suggests that an effector is already present in or on the stem rust urediniospores when they are placed on the leaf surface. However, spores must be alive, as determined by their ability to germinate, in order to elicit RPG1 phosphorylation.

Recent Development of 1,2,4-triazole-containing Compounds as Anticancer Agents

2020 ◽  
Vol 20 (16) ◽  
pp. 1441-1460 ◽  
Author(s):  
Xiaoyue Wen ◽  
Yongqin Zhou ◽  
Junhao Zeng ◽  
Xinyue Liu
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Mechanisms Of Action ◽  
Triazole Derivatives ◽  
Recent Advances

1,2,4-Triazole derivatives possess promising in vitro and in vivo anticancer activity, and many anticancer agents such as fluconazole, tebuconazole, triadimefon, and ribavirin bear a 1,2,4-triazole moiety, revealing their potential in the development of novel anticancer agents. This review emphasizes the recent advances in 1,2,4-triazole-containing compounds with anticancer potential, and the structureactivity relationships as well as mechanisms of action are also discussed.

Synthesis and In Vitro Anticancer Activity of 6-Ferrocenylpyrimidin-4(3H)-one Derivatives

2019 ◽  
Vol 16 (1) ◽  
pp. 160-164 ◽  
Author(s):  
Stanislav A. Grabovskiy ◽  
Rinat S. Muhammadiev ◽  
Lenar R. Valiullin ◽  
Ivan S. Raginov ◽  
Natalie N. Kabal'nova
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Practical Interest ◽  
Breast Adenocarcinoma ◽  
Human Skin Fibroblast ◽  
Normal Human Skin ◽  
Normal Human ◽  
Mcf 7

Aim and Objective: Some ferrocenyl derivatives are active in vitro and in vivo against cancer. Generally, ferrocenyl derivatives for cancer research have three key components: a ferrocene moiety, a conjugated linker that lowers the oxidation potential and some derivative (peptide, nucleobase and others) that can interact with biomolecules. Since the pyrimidine fragment can easily pass through the membrane into the cells and become involved in metabolism; it appears to be promising. Furthermore, this fragment is an electron-acceptor group, so a spacer can be excluded. Therefore, the synthesis of 6-ferrocenylpyrimidin-4(3H)-one derivatives and the study of their anticancer activity have scientific and practical interest. </P><P> Methods: The syntheses of 6-ferrocenylpyrimidin-4(3H)-one derivatives were performed by the condensation of ethyl 3-ferrocenyl-3-oxopropionate with thiourea or acetamidine or guanidine. The cytotoxicity of four 6- ferrocenylpyrimidin-4(3H)-one derivatives was evaluated by using the MTT assay in vitro against Human breast adenocarcinoma MCF-7 and normal human skin fibroblast HSF cells. The tested derivatives induced a concentration-dependent cytotoxic response in cell lines. </P><P> Results: A study of the cytotoxic activity of 6-ferrocenylpyrimidin-4(3H)-one derivatives by the MTT test has found that all compounds have a dose-dependent toxic effect on the lines of breast cancer cells (MCF-7) and normal human fibroblast cells (HSF). The most pronounced cytotoxic effect is exhibited by 2-methyl-6-ferrocenylpyrimidin- 4(3H)-one (MCF-7, IC50 17 ± 1 µM). Conclusion: The experimental results confirm the importance of investigation and design of ferrocenylpyrimidin- 4(3H)-one derivatives as anticancer agents. Compounds where the pyrimidine derivatives are directly linked to the ferrocene unit rather than via a spacer group also may be of interest for antiproliferative drug design.

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