Design, synthesis, and evaluation of novel combretastatin A‐4 based chalcone derivatives as anticancer agents

Rathnakar, Bethi; Kumar, G. Shravan; Mahammad, Saleem P.; Gattu, Sridhar; Kalyani, S; Nimma, Rameshwar; Satyanarayana, Mavurapu

doi:10.1002/jhet.4186

Cited by 8 publications

(2 citation statements)

References 55 publications

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“…As such, several VDAs have been tested in combination with additional therapies, including radiotherapy [ 22 , 23 ], antiangiogenic agents (such as bevacizumab) [ 24 ] and, recently, immunotherapy [ 25 ]. There is a current resurgence of interest in VDAs, and frequent reports describe novel agents, many based on the combretastatin motif [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ], including benzosuberenes [ 37 , 38 , 39 , 40 ]. 2-Methoxy-5-(3′,4′,5′-trimethoxyphenyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ol (also referred to as KGP18; Figure 1 ) has structural similarities to the combretastatins (e.g., the trimethoxyaryl group) and was found to exhibit exceptional biological properties, suggesting it would provide effective tumor vascular disruption.…”

Section: Introductionmentioning

confidence: 99%

Imaging-Guided Evaluation of the Novel Small-Molecule Benzosuberene Tubulin-Binding Agent KGP265 as a Potential Therapeutic Agent for Cancer Treatment

Guo

Wang

Gerberich

et al. 2021

Cancers

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The selective disruption of tumor-associated vasculature represents an attractive therapeutic approach. We have undertaken the first in vivo evaluation of KGP265, a water-soluble prodrug of a benzosuberene-based tubulin-binding agent, and found promising vascular-disrupting activity in three distinct tumor types. Dose escalation in orthotopic MDA-MB-231-luc breast tumor xenografts in mice indicated that higher doses produced more effective vascular shutdown, as revealed by dynamic bioluminescence imaging (BLI). In syngeneic orthotopic 4T1-luc breast and RENCA-luc kidney tumors, dynamic BLI and oxygen enhanced multispectral optoacoustic tomography (OE-MSOT) were used to compare vascular shutdown following the administration of KGP265 (7.5 mg/kg). The BLI signal and vascular oxygenation response (ΔsO2) to a gas breathing challenge were both significantly reduced within 2 h, indicating vascular disruption, which continued over 24 h. A correlative histology confirmed increased necrosis and hemorrhage. Twice-weekly doses of KGP265 caused significant growth delay in both MDA-MB-231 and 4T1 breast tumors, with no obvious systemic toxicity. A combination with carboplatin produced significantly greater tumor growth delay than carboplatin alone, though significant carboplatin-associated toxicity was observed (whole-body weight loss). KGP265 was found to be effective at low concentrations, generating long-term vascular shutdown and tumor growth delay, thus providing strong rationale for further development, particularly in combination therapies.

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Section: Introductionmentioning

confidence: 99%

Imaging-Guided Evaluation of the Novel Small-Molecule Benzosuberene Tubulin-Binding Agent KGP265 as a Potential Therapeutic Agent for Cancer Treatment

Guo

Wang

Gerberich

et al. 2021

Cancers

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“…A range of Combretastatin A-4-based chalones 38 ( Figure 27 ) were synthesised and their antiproliferation of human lung (A549), breast (MCF-7), melanoma (A375) and colon (HT-29) carcinoma cells were examined 87 . Some of them showed significant antiproliferative activity with IC 50 < 2 µM and the compound 38a , the best one, which showed the strongest inhibitory activities against MCF-7 (IC 50 : 10 nM), A375 (IC 50 : 12 nM), and A549 (IC 50 : 65 nM) cell lines, and was 18 times that of CA-4.…”

Section: Aromatic Ring Modificationsmentioning

confidence: 99%

A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors

Liu

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Microtubules play an important role in the process of cell mitosis and can form a spindle in the mitotic prophase of the cell, which can pull chromosomes to the ends of the cell and then divide into two daughter cells to complete the process of mitosis. Tubulin inhibitors suppress cell proliferation by inhibiting microtubule dynamics and disrupting microtubule homeostasis. Thereby inducing a cell cycle arrest at the G2/M phase and interfering with the mitotic process. It has been found that a variety of chalcone derivatives can bind to microtubule proteins and disrupt the dynamic balance of microtubules, inhibit the proliferation of tumour cells, and exert anti-tumour effects. Consequently, a great number of studies have been conducted on chalcone derivatives targeting microtubule proteins. In this review, synthetic or natural chalcone microtubule inhibitors in recent years are described, along with their structure-activity relationship (SAR) for anticancer activity.

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Current scenario of pyrazole hybrids with anti‐breast cancer therapeutic applications

2024

Archiv der Pharmazie

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Breast cancer stands as the leading cause of cancer‐related deaths among women globally, but current therapy is restricted to the serious adverse effects and multidrug resistance, necessitating the exploration of novel, safe, and efficient anti‐breast cancer chemotherapeutic agents. Pyrazoles exhibit excellent potential for utilization as effective anti‐breast cancer agents due to their ability to act on various biological targets. Particularly, pyrazole hybrids demonstrated the advantage of targeting multiple pathways, and some of them, which are exemplified by larotrectinib (pyrazolo[1,5‐a]pyrimidine hybrid), can be applied for breast cancer therapy. Thus, pyrazole hybrids hold great promise as useful therapeutic interventions for breast cancer. The aim of this review is to summarize the current scenario of pyrazole hybrids with in vitro and/or in vivo anti‐breast cancer potential, along with the modes of action and structure–activity relationships, covering articles published from 2020 to the present, to streamline the development of rational, effective and safe anti‐breast cancer candidates.

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Design, synthesis, and evaluation of novel combretastatin A‐4 based chalcone derivatives as anticancer agents

Cited by 8 publications

References 55 publications

Imaging-Guided Evaluation of the Novel Small-Molecule Benzosuberene Tubulin-Binding Agent KGP265 as a Potential Therapeutic Agent for Cancer Treatment

Imaging-Guided Evaluation of the Novel Small-Molecule Benzosuberene Tubulin-Binding Agent KGP265 as a Potential Therapeutic Agent for Cancer Treatment

A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors

Current scenario of pyrazole hybrids with anti‐breast cancer therapeutic applications

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