Read this article to learn about plant derived anti-cancer agents in clinical development.
From Dysoxylum binectariferum Hook, f., Meliaceae family, rohitukine was isolated and this flavonoid structure formed the basis for a novel synthetic flavonoid structure, flavopiridol (Fig. 5.8a).
During a structure activity study over 100 synthetic analogs were synthesized. These analogs were tested against a series of breast and lung carcinoma cell lines, in the course of these studies it was found that they have tyrosine kinase activity and potent growth inhibitory activity.
Flavopiridol showed the most potent activity. In vivo (in mice) broad spectrum activity was found against human tumour xenografts. The NCI then selected it for preclinical and clinical studies in collaboration with the Hoechst Company; currently it is in 18 Phase I and Phase II clinical trials.
Flavopiridol is effectively used alone or in combination with other anticancer agents to treat a broad range of tumours, leukemia, lymphomas and solid tumours. In the 1970s the NCI and United States Department of Agriculture (USDA) were working together with the South Africa Botanical Research Institute on a random collection program.
Combretastatins, a family of stilbenes, were isolated from the South African Combretum caffrum Kuntze, which was collected as part of that random collection program. The genera Combretum and Terminalia both belong to the family Combretaceae that are used for malaria, hepatitis and a variety of other diseases in Indian and African traditional medicine.
Reportedly, several of the Terminalia species have been used for cancer treatment. The combretastatins act as anti- angiogenic agents, they cause tumour necrosis through vascular shutdown in tumours.
One of the water-soluble analogs of the combretastatins, A4 phosphate (CA4) (Fig. 5.8b), has shown promising activity in early clinical trials, and now several mimics are being developed of which three is in clinical trials and another 11 in the preclinical development.
By combining medicinal and combinational chemistry a multitude of analogs were synthesized from this chemical class that served as a model which had a relatively simple natural product structure. All of them containing the crucial trimethoxy aryl moiety linked to substituted aromatic moieties through a variety of two or three atom bridges together with heterocyclic rings and sulfonamides.
Olomucine was first isolated from the cotyledons of Raphanus sativus L. (Brassicaceae) (radish) (Meijer and Raymond, 2003). Olomucine inhibit cycline-dependent kinases (Ddk), proteins which play a major role in cell cycle progression. Roscovitine (derived from olomucine) (Fig. 5.8c) is a more potent inhibitor that resulted from chemical modification.
In Europe, roscovitine is currently in Phase II clinical trials and further development was also taking place within this series of olomucine derived compounds which led to the development of ‘purvalanols’ . Purvalanols is currently undergoing preclinical development because they are even more potent than the natural product olomucine and its synthetic derivative roscovitine.
Today a number of plant derived anticancer agents are available in the market. Their mode of action and target are well known (Table 5.3).