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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The combretastatins (Figure 10.7) are a group of cis-stilbene compounds isolated from the bark and stem wood of the African bush willow tree (Combretum caffrum) that inhibit tubulin polymerization. Structurally, the combretastatin molecules are biaryls connected in the cis- (or Z-) configuration by an ethylene bridge, with Structure-Activity Relationship (SAR) studies showing that the Z-configuration is essential for their antitumor activity. Furthermore, restricted rotation about the olefinic bridge is crucial for biological activity, as is the distance between the two rings. Structures of the combretastatins A-1 and A-4, and related prodrugs CA4P and Oxi4503.
An Introduction to the Ethnopharmacology of Wild Plants
Published in Mahendra Rai, Shandesh Bhattarai, Chistiane M. Feitosa, Ethnopharmacology of Wild Plants, 2021
Shandesh Bhattarai, Christiane Mendes Feitosa, Mahendra Rai
The Combretastatins are a family of stilbenes that act as anti-angiogenic agents resulting in tumor necrosis (Cragg et al. 2002). Combretastatins isolated from the bark of Combretum caffrum showed to be active against colon, lung and leukemia cancers (Petit et al. 1987, Ohsumi et al. 1998). Homoharringtonine isolated from the Cephalotaxus harringtonia is at present in clinical use (Itokawa et al. 2005). Betulinic acid, primarily from Betula species (Cichewitz and Kouzi 2004), but also isolated from Zizyphus mauritiana, Z. rugosa and Z. oenoplia displayed selective cytotoxicity against human melanoma cell lines. Silvestrol from the fruits of Aglaila sylvestre, exhibited cytotoxicity against lung and breast cancer cell lines (Pisha et al. 1995). Other plant derived agents in clinical use are homoharringtonine isolated from Cephalotaxus harringtonia and elliptinium isolated from species of several genera of the Apocynaceae including Bleekeria vitensis, with reputed anti-cancer properties. Several Terminalia species have reportedly been used in the treatment of cancer.
Non-Surgical Management of Thyroid Cancer
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Fosbretabulin, a prodrug of the antimicrotuble-disrupting agent combretastatin was assessed in the randomized phase II functional assessment of cancer therapy (FACT) trial. Unfortunately, the study closed prematurely due to slow patient recruitment but stable disease was seen in 27% with a median survival of 4.7 months and 23% of patients surviving 1 year.95
Design, synthesis and biological evaluation of novel diarylpyridine derivatives as tubulin polymerisation inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Shanbo Yang, Chao Wang, Lingyu Shi, Jing Chang, Yujing Zhang, Jingsen Meng, Wenjing Liu, Jun Zeng, Renshuai Zhang, Yingchun Shao, Dongming Xing
Combretastatin A-4 (1, Figure 1) is a natural product, first extracted from the bark of the South African willow tree Combretum caffrum in 1989, that inhibits tubulin polymerisation by interacting with colchicine binding site on tubulin.7 This cis-stilbene shows excellent cytotoxicity against a wide range of human cancer cell lines, including multidrug-resistant cancer cell lines.8,9 CA-4P (2, Figure 1), its soluble prodrug, is currently under clinical investigation as a combination therapy for various multidrug-resistant solid tumours.10 Due to the structural simplicity of CA-4, numerous structure-activity relationships (SAR) studies have been performed on this compound and its analogs by many academic and industrial groups. SAR studies have shown that the cis-orientation of the double bond and the presence of 3,4,5-trimethoxyphenyl as ring A are essential to produce potent potency.11 A ring is an essential requirement for potent cytotoxicity. Unfortunately, CA-4 and other olefinic analogs are prone to isomerise to inactive trans-forms during storage and administration.12 In order to avoid the stability problems of CA-4, the olefinic groups of the A and B rings are fixed by introducing various cyclic structures such as three, five and six-membered rings.13–15
Combretastatin-based compounds with therapeutic characteristics: a patent review
Published in Expert Opinion on Therapeutic Patents, 2019
Lalit Mohan Nainwal, Mohammad Mumtaz Alam, Mohammad Shaquiquzzaman, Akranth Marella, Ahmed Kamal
Molecular hybridization in medicinal chemistry is a well-established promising approach to derive more potent molecules than their parent molecules. In molecular hybridization, two privileged pharmacophores of two active molecules are coupled and is a hot topic in medicinal chemistry. This approach has also been explored by various researchers. Apart from this, combretastatin derivatives could be given in combination with the other established anticancer drug to maximize and enhance their anticancer potential. The vascular disrupting potential and anti-tubulin activity are like two edges sword which are tumor selective and may prove beneficial in destructing the survival potential and favorable microenvironment which favor tumor nourishment and proliferation. Therefore, authors suggests further research in formulating new pharmaceutical formulations comprising of combretastatin A-4 or other combretastatin derivatives with other clinical anticancer drugs. In past, pharmaceutical formulations comprising of single or different prodrugs of combretastatins were tried.
Leukemia Chemoprevention and Therapeutic Potentials: Selected Medicinal Plants with Anti-Leukemic Activities
Published in Nutrition and Cancer, 2022
While the medicinal plants in this review have shown well In Vitro efficacy against leukemia and other cancer cell lines, efforts at entering them into leukemia clinical trials have been slow. Recently, a phase 1 b clinical trial of combretastatin A1 and cytarabine combination in relapsed/refractory AML patients showed some good clinical response [107]. A derivative of parthenolide has also been shown to have good activity against human AML cells, but unfortunately, it is being trialed for a solid tumor [108]. It is hoped that some of the natural products in the medicinal plants in this review would soon be entered into a leukemia clinical trial.