Rohitukine and Forskolin

Abstract

Rohitukine is the anti-inflammatory principle of Dysoxylum binec tariferum. Forskolin is the unique adenylate cyclase-activating prin ciple of Coleus forskohlii. The cyclic AMP-dependent effects it is known to display are now supplemented by newly discovered cyclic AMP-independent effects. Synthetic and structure-activity relationship studies leading to the development of antiinflammatory, im munomodulatory and anticancer rohitukine analogs, and intraocular pressure-lowering and cardiotonic forskolin analogs are described. A pathway to a forskolin-based antithrombotic phytotherapeutic product is also presented.Our updated findings on the discovery and development of novel human medicinal agents from plants are described herein. These findings represent the current status of a venture that commenced in India over 20 years ago in the 1970s. The objectives, strategies, and results of this sustained mission-oriented venture have been adequately documented (1-5). The venture was sustained in an era when related natural productsoriented efforts were generally at their ebb in the pharmaceutical industry and there was regrettably seen the discontinuation or diminution of ventures worldwide, like that of the Roche Research Institute, Australia, the National Cancer Institute, U.S.A., and the Ciba Research Centre, India. Even in today's era of the 1990s, with the revival of such programs at the National Cancer Institute, U.S.A. and in industry, the realistic picture to be faced is that about the only plant-based novel chemical entities that have emerged as innovative medicines on die market after reserpine are the an ticancer drugs, vincristine, vinblastine, etoposide and taxol. Our venture at Hoechst, aimed at converting plant constituents into novel drugs, owes its sustenance principal ly to our discovery of molecules like rohitukine and forskolin. The new chemical en tities (NCEs) and a potential phytotherapeutic product which have been derived from them are shown in Table I. Rohitukine-Derived HL 275 and HIL 8276Compound HL 275 (designated in the earlier literature as L 86 8275) moved into development as a potential anticancer agent as a consequence of an evolution of events commencing with the isolation of the naturally-occurring chromone 0097-6156/93/0534-0331S06.00A)

Plants as Sources of Drugs

“…This compound exhibits potent adenylate cyclase activating activity, and has been found to have hypotensive properties, with cardiotonic, platelet-aggregation inhibitory, and spasmolytic effects (28,29). While the Biol.ogical activities of the parent compound have been known for some time, a number of forskolin analogs with potential for drug use have been developed in Ind.ia (29). Of these, NKH 477 (18) is a derivative with an aminoacyl substituent that is water-soluble and is undergoing clinical trial in Japan, in the form of its hydrochloride salt, as a cardiotonic.…”

“…Of these, NKH 477 (18) is a derivative with an aminoacyl substituent that is water-soluble and is undergoing clinical trial in Japan, in the form of its hydrochloride salt, as a cardiotonic. HIL 568 (19) reduces the intraocular pressure of rabbits, and is being developed for the treatment of glaucoma (29). …”

“…EGb 761 is an extractive of G. biloba leaves produced with acetone and water, followed by the removal of strongly lipophilic compounds and condensed polyphenols, and it has been suggested that it is the combined effects of the various leaf secondary metabolite constituents which are responsible for the observed clinical activities of Ginkgo. These constituents are complex and embrace various terpenoid lactones [e.g., ginkgolides A-C, J and M (26)(27)(28)(29)(30) and bilobalide (31)], biflavonoids (e.g., armentoflavone, 32; bilobetin, 33; ginkgetin, 34; isoginkgetin, 35; sciadopitysin, 36; 5'-methoxybilobetin, 37), as well as flavonol glycosides (e.g., mono-, di-, and triglycosides of kaempferol, isorhamnetin, and quercetin), coumaric acid esters of flavonols, and other phenols (39)(40)(41). The standard plant extract EGb 761 contains 24% w/w of flavonoids and 6% w/w of terpene lactones (39).…”