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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.
The oxygen effect and therapeutic approaches to tumour hypoxia
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Michael R. Horsman, J. Martin Brown, Albert J. van der Kogel, Bradly G. Wouters, Jens Overgaard
The inadequate vascular supply to tumours is one of the major factors responsible for the development of hypoxia. The tumour vasculature develops from normal tissue vessels by the process of angiogenesis. This is an essential aspect of tumour growth, but this tumour neo-vasculature is primitive and chaotic in nature and is often unable to meet the oxygen demands of rapidly expanding tumour regions, thus causing hypoxia to develop. The importance of the tumour neo-vasculature in determining growth and the environmental conditions within a tumour therefore makes it an attractive target for therapy (20). The first and most popular is the use of drugs to prevent angiogenesis from occurring (angiogenesis inhibitors [AIs]), while the second involves the use of therapies that can specifically damage an already established vasculature (vascular disrupting agents [VDAs]). Examples of AIs clinically tested include inhibitors of vascular endothelial growth factor such as bevacizumab; tyrosine kinase inhibitors including sorafenib (Bay 43-9006/nexavar), sunitinib (SU11248/sutent), vanatanib (PTK787/ZX 222584) and vandetanib (ZD6474/zactima); and thalidomide and related analogues (lenalidomide, pomalidomide). Clinically relevant VDAs include tubulin binding agents like combretastatin A-1 phosphate, OXi4503, ombrabulin (AVE8062) and plinabulin (NPI-2358); the flavonoid compound vadimezan (ASA404); and chemotherapeutic drugs such as the vinca alkaloids and arsenic trioxides.
Application of Phytodrug Delivery in Anticancer Therapy
Published in Madhu Gupta, Durgesh Nandini Chauhan, Vikas Sharma, Nagendra Singh Chauhan, Novel Drug Delivery Systems for Phytoconstituents, 2020
The first (1973) gathering of Combretum caffrum in Africa for the National Cancer Institute (NCI) in the former Rhodesia (now Zimbabwe) led to the discovery of combretastatins. Pettit and coworkers successfully isolated the first constituent of Combretum caffrum combretastatin in 1982 (Pinney et al., 2005), and the absolute stereochemistry was confirmed as R-configuration in 1987 (Pettit et al., 1987). Based on the structural features, combretastatins can be generally classified into four categories: A-Series (cis-stilbenes), B-series (diaryl-ethylenes), C-series (quinone), and D-series (macrocyclic lactones). Several natural compounds separated from Combretum caffrum present excellent inhibition capacity against tubulin assembly and human cancer cell lines, significant vascular targeting effects, and prominent antiangiogenesis activity (Lippert, 2007), such as (−)combretastatin, combretastatin A-1/A-4/A-6, combretastatin B-1, combretastatin D-1, phenanthrene, and dihydrophenanthrene, with combretastatin A-4 (CA4) presenting the strongest effect. Poor water solubility of CA4 precluded its further application, but its water-soluble derivative, CA4 phosphate, has been broadly applied in the therapy against a series of thyroid cancers, lung cancer, ovarian cancer, etc., alone or combined with other chemotherapeutics (Nathan et al., 2012, Rustin et al., 2010, Siemann et al., 2009). The plant source of combretastatins, the chemical structure of CA4, and its derivative CA4 phosphate are shown in Figure 9.5. Moreover, various combretastatin derivatives have been developed, some of which have already reached clinical trials (Hinnen and Eskens, 2007) and many others are in the preclinical period as potential anticancer agents (Shan et al., 2011). For example, a suite of 1,2,3-thiadiazole derivatives from combretastatin are synthesized and assessed for their anti-proliferation activities; the six most cytotoxic derivatives were then assessed for their inhibition activities on tubulin polymerization, and similarly strong inhibitory effects with CA4 were observed (Wu et al., 2007).
Discovery of new quinolines as potent colchicine binding site inhibitors: design, synthesis, docking studies, and anti-proliferative evaluation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Mohamed Hagras, Moshira A. El Deeb, Heba S. A. Elzahabi, Eslam B. Elkaeed, Ahmed B. M. Mehany, Ibrahim H. Eissa
Colchicine binding site inhibitors (CBSI) produce their biological activities by suppressing the vital process of tubulin assembly, and consequently suppressing microtubule formation14. Colchicine I, the most famous inhibitors in this category, binds to tubulin very tightly, but there is no any compound in this group has a significant use in treatment of cancer16. combretastatin A-1 (CA-1) II and combretastatin A- 4 (CA-4) III are combretastatin analogs having microtubule inhibitory activity with limited value due to their low water solubility17. To improve their water solubility, such analogs were designed as prodrugs of monosodium phosphate salt. These prodrugs can be metabolised in vivo into CA-1 and CA-4 as active components18,19. CA-4P showed no bone marrow toxicity, stomatitis, and hair loss in phase II clinical trial20. One of CA-4 analogs is ombrabulin IV which has better water solubility, oral activity, enhanced anti-cancer activity and decreased adverse effects14.
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
Macrocyclic lactones combretastatin D-1 and combretastatin D-2 were first isolated [3] from the stem wood of Combretum caffrum by Pettit et al. and patented in US4940726A patent [63]. Combretastatin A-4 was patented [64] in 1991(US4996237) by them. They also patented (US005409953A, US005569786A) method of isolation and synthesis [65,66] of antineoplastic compounds combretastatin A-1, combretastatin A-2, combretastatin A-3, combretastatin B-1, combretastatin B-2, combretastatin B-3, and combretastatin B-4 in 1995. Whereas, disodiumphosphate, dipotassium phosphate, and ammonium phosphate prodrugs of combretastatin A-4 with their anticancer potentials were described in a patent US005561122A in 1996 [67].
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.