Hydroxylation activated prodrugs

Details Hydroxylation activated prodrugs Hydroxylation activated prodrugs

1998-07-14

2001-04-10

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ketone doai

Reexamination Certificate

active

06214886

ABSTRACT:

The present invention concerns enzymatic aromatic hydroxylation-activated prodrugs, particularly anti-tumour prodrugs and those which are specifically activated by the hydroxylation activity of the enzyme CYP1B1.
Many conventional cytotoxic drugs are known which can be used for chemotherapeutic purposes. However, they typically suffer from the problem that they are generally cytotoxic and therefore may effect cells other than those which it is wished to destroy. This can be alleviated somewhat by using targetted drug delivery systems, for example direct injection to a site of tumourous tissue, or by e.g. binding the cytotoxic agent to antibody which specifically recognises an antigen displayed by cancerous cells. Alternatively, electromagnetic radiation may be used to cause chemical changes in an agent at a desired site in the body such that it becomes cytotoxic. However, all of these techniques have, to a greater or less extent, certain limitations and disadvantages.
It has been reported (Murray, G. I. et al., Jul. 15, 1997, Cancer Research, 57: 3026-3031) that the enzyme CYP1B1, a member of the cytochrome P450 family of xenobiotic metabolizing enzymes, is expressed at a high frequency in a range of human cancers including cancers of the breast, colon, lung, oesophagur, skin, lymph node, brain and testis, and that is it not detectable in normal tissues. This led to the conclusion (p. 3030, final sentence) that “. . . the expression of CYP1B1 in tumour cells provides a molecular target for the development of new anticancer drugs that could be selectively activated by the presence of CYP1B1 in tumour cells”. No specific anticancer drugs are suggested.
The present invention have now succeeded in creating a range of prodrugs which have little or negligible cytotoxic effect when in their normal state, but which are highly cytotoxic (i.e. have a substantially increased cytotoxicity) when hydroxylated by CYP1B1. This provides for a self-targetting drug delivery system in which a non-cytotoxic (or at least negligibly cytotoxic) compound can be administered to a patient, for example in a systemic manner, the compound then being hydroxylated at the site of tumour cells (intratumoural hydroxylation) to form a highly cytotoxic compound which acts to kill the tumour cells. The fact that CYP1B1 is not expressed by normal cells means that the hydroxylation of the compound only occurs at the site of tumour cells and therefore only tumour cells are affected, thus providing a self-targetting drug delivery system.
The prodrugs of the present invention have the distinct advantage of being useful in the treatment of tumours at any site in the body, meaning that even tumours which have undergone metastasis (which are not normally susceptible to site-specific therapies) may be treated, as well of course as primary and secondary tumours.


REFERENCES:
patent: 5276058 (1994-01-01), Satoh et al.
patent: 5430062 (1995-07-01), Cushmann et al.
patent: 0322738 (1989-07-01), None
Chemical Abstracts, vol. 53, No.9, Abstract 9122, May 1959.*
Klein, Chemical Abstracts, vol. 120, No. 1, Abstract No. 14,657c p. 422, Jan. 1994.*
Tully et al, Journal of Organometallic Chemistry, vol., No. 1, pp. 75-92, 1995.*
Cushman M. et al.: “Syntheisis and Evaluation of Analogues of (Z)-1-(4-Methoxyphenyl)-2-(3,4,5-Trimethoxyphenyl) Ethene As Potential Cytotoxic and Antimitotic Agents”; Journal of Medicinal Chemistry, vol. 35, No. 12, Jun. 12, 1992, pp. 2293-2306, XP000571677; see tables, I, II, IC.
George R. Pettit et al.: “antineoplastic Agents 322. Synthesis of Combretastin A-4 Produgs”; Anti-Cancer Drug Design, vol. 10, 1995, pp. 299-309, XP002102893 see p. 299, line 1-p. 301, line 17 see page 307, line 40-p. 308, line, 12.
Patent Abstracts of Japan; vol. 096, No. 011, Nov. 29, 1996 & JP 08 188546 A (Kyowa Hakko Kogyo Co Ltd), Jul. 23, 1996 see abstract.
Sajjat Hussoin et al.: “Polyhydroxylated Phenylacrylic Acid Derivatives as New Anti-tumor Agents”; Journal of Pharmaceutical Sciences, vol. 80, No. 5, May 1991, pp. 416-418, XP002102894; Washington, US; see p. 417, col. 1, line1—p. 418, col. 2, line 38.
Koji Ohsumi et al.: “Novel Combretastatin Analogues Effective against Murine Solid Tumors: Design and Structure-Activity Relationships”; Journal of Medicinal Chemistry., vol. 41, No. 16, Jul. 30, 1998, pp. 3022-3032, XP002102895; Washington US; see p. 3025, col. 1, line 4—p. 3028, col. 1, line 2; table 1.
Ducki S. et al., “Potent antimitotic and cell growth inhibitory properties of substituted chalcones”; Biorganic & Medicinal Chemistry letters, vol. 8,No. 9, May 1, 1998, p. 1051-1056 XP004137018; see tables 1-3, compounds 2a, 5a; figure 1.
Patent Abstracts of Japan; vol. 010, No. 245 (C-368), Aug. 22, 1986 & JP 61 076433 A (Toyobo Co Ltd), Apr. 18, 1986 see abstract.
Chemical Abstracts, vol. 68, No. 5, Jan. 29, 1968; Columbus OH, US; abstract No. 21141r, G. Pappalardo et al.: “Relation between Structure and Antibacterial Action of Arylthioamides, II. Antibacterial Activity, Ultraviolet and Infrared Spectra, and Acid Hydrolysis of Aryl- and Arylvinylenethioamides” p. 2014; col. 2; XP002102896 see abstract & Farmaco, ed. Sci., vol. 22, No. 10, 1967, pp. 808-820.

Affiliated with

Also associated with

Rating

Hydroxylation activated prodrugs does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Hydroxylation activated prodrugs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hydroxylation activated prodrugs will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2541162