Antineoplastic Agents. 454. Synthesis of the Strong Cancer Cell Growth Inhibitors trans-Dihydronarciclasine and 7-Deoxy-trans-dihydronarciclasine

Abstract

To further pursue the antineoplastic leads offered by our isolation of trans-dihydronarciclasine (1a) and 7-deoxy-trans-dihydronarciclasine (1c) from two medicinal plant species of the Amaryllidaceae family, a practical palladium-catalyzed hydrogenation procedure was developed for synthesis of these isocarbostyrils from narciclasine (2a) and 7-deoxynarciclasine (2c).From a 1982 collection (bulbs) of the Chinese medicinal plant Zephyranthes candida (Amaryllidaceae) 1b we isolated the strong (ED 50 0.0032 μg/mL) P388 lymphocytic leukemia cell growth inhibitor trans-dihydronarciclasine (1a). The structure was established by detailed spectroscopic analyses of its peracetate derivative (1b) 1b and confirmed by comparison with the minor product from catalytic hydrogenation of narciclasine (2a). 2 Hydrogenation afforded as the major product the expected cis-dihydronarciclasine (3a) accompanied by the trans isomer (1a) and iso-narciclasine (4a). Subsequently, trans-dihydronarciclasine (1a) was found to exhibit strong cancer cell growth inhibition (mean panel GI 50 12.6 nM) against the U.S. National Cancer Institute (NCI) panel of cancer cell lines3a,b whereas its cis isomer (3a) 3c was only very weakly active (mean panel GI 50 3800 nM). Importantly, the trans isomer (1a) gave an active Compare correlation coefficient of 0.92 in respect to (+)-pancratistatin (5). 3a The trans isomer (1a) also showed strong activity against a range of RNA viruses while the synthetic cis isomer (3a) was completely inactive. 4 Because of the close structural and biological relationship of trans-dihydronarciclasine (1a) to (+)-pancratistatin (5), already in preclinical development, it became necessary to increase the availability of trans isomer 1a and the closely related 7-deoxy-trans-dihydronarciclasine (1c), by synthesis. The latter was isolated from Hymenocallis sp. (P388 ED 50 0.02 μg/mL) and gave an active Compare correlation coefficient of 0.89 in respect to (+)-pancratistatin (5). 3 Those structural and biological relationships of 1a and 1c to (+)-pancratistatin (5) are of special importance owing to its well known 5 in vitro and in vivo anticancer activity augmented by the rapidly increasing knowledge of the very promising activation of the mitochondrial route to cancer cell apoptosis.6a Importantly, pancratistatin has been shown to induce apoptosis routinely in various cancer cell lines at sub-micromolar concentrations while being nontoxic to normal human fibroblasts and endothelial cells at the same drug concentrations.6b,c As anticipated, narciclasine (2a) has recently been found to induce the mitochondrial and/or caspase-8/caspase-10 death receptor pathway in human MCF-7 breast as well as PC-3 prostate cancer cell lines. 5 Presumably, the strong cancer cell growth inhibitors 1a and 1c will also display related mechanisms of action selectively targeting cancer cells. The need to begin more detailed preclinical development of 1a and 1c led to our syntheses of the potentially useful phosphate prodrugs trans-dihydronarcis...

Narciclasine as well as other Amaryllidaceae Isocarbostyrils are Promising GTP‐ase Targeting Agents against Brain Cancers

“…In a recent study, McNulty et al have demonstrated that narciclasine displays potent inhibitory activity against the human cytochrome CYP3A4, while trans ‐dihydronarciclasine is inactive with respect to CYP3A4, CYP19, and CYP1A1. The authors concluded that trans ‐dihydronarciclasine is a readily available substance with potent and selective anticancer activity, which is consistent with earlier results from the Pettit laboratory …”

Targeting of eEF1A withAmaryllidaceaeisocarbostyrils as a strategy to combat melanomas

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Pancratistatin Selectively Targets Cancer Cell Mitochondria and Reduces Growth of Human Colon Tumor Xenografts

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