A novel antiproliferative drug and methods are disclosed. The drug has the general structural formula: ##STR1## where R1=OR.sub.1 ', SR.sub.1 ', or N(R.sub.1 'R.sub.1 ").sub.2, where R.sub.1 ' and R.sub.1 " are H or lower alkyl groups, and R.sub.2 is an acylamino, or aroylamino group. The compound is useful for inhibiting cell proliferation in drug-resistant tumor cells. Also disclosed is a method of chemical converting a colchicine derivative to form an active inhibitor of DNA topisomerase II.
The present invention relates to novel colchicine derivatives having antiproliferative, antineoplastic, antiinflammatory and muscle relaxant activities; said derivatives include novel colchine nitrogen amides for use either as such or after derivatization of the hydroxyl at C.sub.3 of the aromatic ring and at C.sub.10 of the tropolone ring. These novel compounds have a cytotoxicity on human tumoral cell lines comparable with colchicine but, in comparison with the latter, they are much more active on cells resistant to the usual antiblastics. The compounds can be included in pharmaceutical formulations useful for the intravenous, oral and topical administrations.
##STR1## N-deacetyl-thiocolchicine and 10-deacetyl-baccatin III derivatives of formula (I) wherein R and n have the meanings specified in the disclosure, are valuable antitumoral drugs.
Novel tricyclic compounds of formula I as defined in the specification, a process for their preparation and their use for the preparation of optically active or racemic colchicine and thiocolchicine derivatives.
A method of modulating the activity of a aberrant cell topoisomerase enzyme involving contacting the enzyme with a compound that inhibits enzyme-mediated cleavage of a polynucleotide substrate with which the enzyme is in complex. Pharmaceutical compositions containing such compounds may be used to treat neoplasias or to inhibit the growth of certain cancer cells. Screening methods can be employed to identify other compounds for these uses.
