Substituted stilbenes and their reactions

Abstract

The present invention relates to stilbene and quinine compounds related to combretastatin A-4 and their use as anticancer compounds and prodrugs. The compounds include those with an alkyl group on the double bond of cis or trans-stilbenes, compounds with one or more (and preferably 2 or 3) alkyl group substituents on the stilbene a ring, compounds with an alkoxy group other than methoxy at position 3, 4 and / or 5 of the stilbene A ring, compounds (or prodrugs) in which BOC amino acid esters are formed with the phenolic hydroxyl at the 3-position of the B ring and compounds (or prodrugs) based on a benzoquinone B ring. The present invention further relates to the photochemical reactions of stilbene compounds, either the above compounds disclosed for the first time herein or compounds based on prior art stilbenes. These reactions include the photochemical release of an active form of the compound from a prodrug conjugate and the photochemical isomerisation of the compounds, especially from a trans to cis form of compounds. The reactions can be used alone or in combination to convert inactive or comparatively less active forms of the compounds to more active forms, thereby allowing the compounds to be selectively targeted, e.g., activating them at the site of a tumour.

Description

FIELD OF THE INVENTION [0001] The present invention relates to novel compounds, and more particularly to stilbene and quinone compounds related to combretastatin A-4 and their possible use as anticancer compounds and prodrugs. In further aspects, the present invention relates to the photochemical reactions of some of these compounds, in the photochemical isomerisation of the compounds and / or the photochemical release of an active compound from a protected compound (prodrug). BACKGROUND OF THE INVENTION [0002] The stilbene cis-combretastatin A-4 Z-1, isolated from the African bush willow, Combretum caffrum shows exciting potential as an anticancer agent, binding strongly to tubulin and displaying potent and selective toxicity toward tumour vasculature (U.S. Pat. No: 4,996,237, Arizona Board of Regents, Pettit et al, Experimentia, 1989, 45, 209; Lin et al, Mol. Pharmacol., 1988, 34, 200; Grosios et al, Brit. J. Cancer, 1999, 81, 1318; Lin et al, Biochemistry, 1989, 28, 6984; Woods et ...

AI Technical Summary

Benefits of technology

[0079] In a further aspect, the present invention provides the compounds as defined herein for use in a method of medical treatment. In preferred embodiments, the present invention provides the use of the compounds defined herein for the preparation of a medicament for the treatment of a condition that is ameliorated by administration of the activated or released form of the compound. In such uses, it is preferred that the activated form of the compound has significantly greater activity than the protected form of the compound, e.g. making it possible to obtain selectivity in the delivery and activation of the compound, e.g. to a target tissue. In preferred embodiments of the invention, the compounds are employed in medicaments for the treatment of cancer.

[0090] The work disclosed herein arises from the findings that the inactive trans isomer of combretastatin A-4 E-1 can be converted to the active cis-isomer Z-1 by the action of ultraviolet light ex situ in a photochemical reactor. The irradiation of E-1 in this manner leads to an impressive and rapid increase in activity. Further we have found that only after a long period of irradiation is the formation of the phenanthrene (which is only moderately active, as measured by its ability to inhibit cancer cell growth in vitro, IC50 0.7 μM) evident. We have prepared phenanthrene, by irradiation of E-1, in good yield when an oxidant (I2) is present (to oxidize the first-formed cyclization product). This provides an opportunity to exploit the hypoxic nature of solid tumours and increase the selectivity of irradiated E-1. In other words, healthy cells may provide an oxidative pathway for the formation of the less toxic phenanthrene and effectively decrease the lifetime of Z-1.

[0091] The same result can be achieved in situ in the presence of cultured cancer cells (K562 human myelogeneous leukaemia cell line. These experiments showed that within 2 seconds of exposure to ultraviolet light the activity of the E-combretastatin A-4 (IC50 originally 5 μM) increases to 2 nM, providing a rapid thousand-fold increase in activity. Moreover, the cells in the absence of the drug are not affected by exposure to the radiation and grow normally over the 5 days of the assay. To increase the water solubility of the drug we have produced prodrugs with a photo-cleavable group attached to the B-ring phenolic OH group. The nitro vanillin derivative was chosen since it has been used as a photo-cleavable linker for solid phase synthesis applications and its synthesis is relatively simple. These prodrugs have been successfully cleaved in both the E and Z series (E-6 and Z-6 respectively) and have produced highly cytotoxic agents in vitro upon in situ exposure to ultra violet radiation. The cleavage of the water solubilising group appears to be faster than the E→Z isomerisation, at least under ex situ irradiation. Thus, the use of Z-6 has some merit. Indeed it forms the prototype for systems that do not rely on any special photochemical features of the molecule to be delivered. This provides a more general approach to the site-specific photochemical activation of prodrugs. Moreover, the photocleavable water solubilising group can be engineered, so that cleavage occurs at longer wavelength and rapidly.

Problems solved by technology

The use of Z-1 as a clinically useful anticancer agent has been severely hampered by its poor water solubility (Brown et al, J. Chem. Soc., Perkin Trans.

In addition, disruption of the intracellular microtubule networks by combretastatin A4 leads to the destruction of microvessels within the tumour.

However, it remains a problem in the art in designing effective compounds and especially those which can be selectively targeted.

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