Podophyllotoxin dimer as DNA topoisomerase II inhibitors,...

Details Podophyllotoxin dimer as DNA topoisomerase II inhibitors,... Podophyllotoxin dimer as DNA topoisomerase II inhibitors,...

2000-12-22

2002-08-27

Trinh, Ba K. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S326000

Reexamination Certificate

active

06441198

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the synthesis of new podophyllotoxin dimers as DNA-topoisomerase II inhibitors.
The present invention particularly relates to the synthesis of a new class of 4&bgr;-arylamio dertives of the podophyllotoxin dimers as potent inhibitors of DNA-topoisomerase II and as useful antitumour agents.
BACKGROUND OF THE INVENTION
Podophyllotoxin is a plant toxin that inhibits the assembly of microtubules. It was first isolated from the North American plant
Podophyllum peltatum linnaeus
, commonly known as the American Mandrake or May Apple [Padwyssotzki V.
Arch Exp. Pathol. Pharmakol
. 1880, 13, 29]. The naturally occurring atyltetralin lignans of podophyllotoxin and desoxypodophyllotoxins have been attempted in the treatment of human neoplas. These have been mostly unsuccessful and complicated by side effects such as nausea, vomiting, diarrhea and damage to normal tissues [Jardin, I. Podophylitoxins, in Anticancer Agents Based an Natural Product Models: Casady, J. M.; Douras, J. D.; Eds; Academic Press: New York, 1980, pp,319-351]. Extensive structural modifications of podophyllotoxin ring system have been performed in order to obtain more potent and less toxic anticancer agents, which resulted in the synthesis of etoposide and teniposide. These two semi-synthetic glycoside derivatives of podophyllotoxin have been shown to be active in the treatment of a member of cancers including Moms, acute leukemia, cancers of the lung, ovary, test bladder and brain and kaposis sarcoma associated with the acquired immune deficiency syndrome [Sackett. D.L. Podophyllotoxin, Steganacin and Cambratastain Natural Products that Bind at the Colchicine Site of Tubulin,
Pharm. Ther
. 1998, 59, 163-228].
Etoposide (VP-16) is a widely used antineoplastic agent. The mechanism of action of this drug is due to its ability to inhibit the enzyme DNA-topoisomerase It by stabilizing a cleavable enzyme DNA complex in which the DNA is cleaved and covalently linked to the enzyme [Ross, W. Rowe, T.; Glisson, B.; Yalowch J.; and Liu, L. Role of Topoisomerase II in Mediating Podophyllotoxin-Induced DNA Cleavage,
Cancer Res
.; 1984,44: 5857-5860].
The structural modifications of podophyllotoxin and desoxypodophyllotoxin have led to some non-sugar substituted analogues particularly nitrogen containing derivatives as 4&bgr;-N-alkylamino/arylamino compounds of 4′-demethylepipodophyllotoxin. These are as active or more active than etoposide in their inhibition of the human DNA topoisomerase II. Amongst these N-linked congeners NPF [4′-0-demethyl-4&bgr;-(4″-fluoroanilino)-4-desoxypodophyllotoxin] and W-68 [4′-0-demethyl-4&bgr;-(4″-nitroanilino)-4-desoxypodophyllotoxin] have been shown better anticancer activity in their preclinical studies [Zhang, Y. L.; Tropsha, A.; Mephenol, A. T.; Lee, K-H.,
J. Med Chem
. 1994, 37, 1460]. NPF is the most active drug which is having 10-fold more potency in inhibiting human DNA topoisomerase II and 113 times more activity in cellular protein-DNA complex formation when compared to etoposide. In the in vitro human tumour cell lines assay, it has proven to be very active.
The structure activity relationship studies, revealed the following features
(i) the presence of a 4′-phenolic hydroxyl group.
(ii) maintenance of an intact methylenedioxy system of ring A
(iii) the free rotation of E-ring
(iv) a —N atom containing at CA4&bgr;-position.
The drawbacks of the referred work are that in the treatment of human neoplasia, they have been found to be mostly unsuccessful and complicated by the side effects such as nsea vomiting diarrhea and damage to normal tissues. These significant findings prompted to synthesize a new class of 4-arylnmino derivatives of the podophyllotoxin dimers as potent inhibitors of DNA-topoisomerase II and as useful antitumour agents.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide novel podophyllotoxin dimers as DNA topoisomerase II inhibitors.
Another object of the present invention is provide a process for the synthesis of new podophyllotoxin dimers as DNA topoisomerase II inhibitors, which obviates the drawbacks as detailed above.
Another object of the present invention is to provide a novel and stereo-selective dimers of the podophyllotoxins and 4′-O-demethylepidophyllotoxin in good yields.
Still another object of the present invention is to provide the key step for the synthesis of these dimers by direct nucleophilic substitution of the C-40&bgr;-bromo intermediates.
SUMMARY OF THE INVENTION
The above and other objects of the present invention are achieved by providing the new class of C-4&bgr;-arylsubstituted N-inked dimers of podophyllotoxin and 4′-O-demethyle pipodophyllotoxins which have been synthesized as DNA-topoisomerase II inhibitors shown in
FIG. 1
of the accompanying drawings.
Accordingly, the present invention provides Novel podophyllotoxin dimers having structural formula 3-8.
wherein R is H or CH
3
and Z is an aryl or substituted aryl compound selected from the group consisting of phenylene, naphtlalene, p-terphenyl dimethoxy benzidine and diphenyl ether.
The present invention also provides a process for preparing new podophyllotoxin dimers as claimed in claim
1
, said process comprising
(a) stirring a solution of aromatic diamine, a base and a phase transfer catalyst in a dry organic solvent at temperature in the range of −10 to 30° C.;
(b) adding slowly 4&bgr;-bromo podophyllotoxin to the above solution;
(c) stirring the above reaction mixture continuously for a time period ranging between 6 to 12 hrs;
(d) evaporating the solvent by known methods; and
(e) dissolving the residue in a polar solvent followed by washing and separating the product by conventional methods.


REFERENCES:
patent: 5880131 (1999-03-01), Greenwald et al.

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