Aziridine and hydroxy- and chloroethylamine derivatives of colchicine and their biological activity

Abstract

546.944.615 With the aim of enhancing the cytostatic properties of the initial alkaloid, new aziridine and bis (chloroethyl) A fall in toxicity in comparison with the initial alkaloids has been reported for a series of colchicine and colcbamine derivatives [1, 2]; however, their antimm~al activity is not always retained. It is known that the introduction of alkylaling fragments (aziridine, bis(chlcxoethyl)amine, etc.) into such carrier molecules as amino acids, nucleotides, sugars, hccmones, and a number of others improves or ensures their antitumoral activity [3].We have introduced aziridine and chioroethylamine substituents into the colchicine molecule with the aim of enhancing its ant.immoral activity by cc~nbining the tubnlin-interactive effect of colchicine and the alky]ating action of the fragments introduced.10-Chloroethylamino-10-demethoxycolchicine (4) was obtained by two methods: by the reaction of colchicine with chloroethylamine hydrochloride in an alkaline medium and from lO-hydroxyethylamino-lO-demethoxycolchicine (2) by indirect chlorination.

Colchicine Alkaloids and Synthetic Analogues: Current Progress and Perspectives

“…As a rule, the advantage of such aza-colchicines results from the fact that the biological activity is maintained, while the compounds are less exposed to P-glycoprotein (P-gp), causing the development of multidrug resistance. 159 The known members of this compound family are derived either from ammonia (with a free NH 2 group), 160 mono-or disubstituted alkylamines, 161,162 allyl or propargylamine, 163 aromatic amines, 161,164 amino acids, 165 ethanolamine, 166 morpholine, or piperazine. 161 Azacolchicinoids of type 194 with small amino substituents X, such as NHMe (194k) or NHEt (194l), display a strong cytotoxicity based on inhibition of tubulin polymerization.…”

Aziridine alkaloids as potential therapeutic agents

“…These compounds had an increased radiomodifying and antitumoral activity and a decreased toxicity compared with the initial colchicine. Results obtained in the National Cancer Institute of the USA from the study of the cytostatic activity of 133 and bis(chloroethyl)amino derivatives on 60 tumor lines were reported [160]. Originally colchicine a soluble alkaloid was extracted from Colchicum autumnale also known as autumn crocus, meadow saffron or itkuchala in Uzbekistan which means 'dog poison' [160].…”

β-Phenylethylamines and the isoquinoline alkaloids (July 1999 to June 2000)

“…406 The pharmacological properties and physiological effects of the following have also been studied: 3,6-O-diacetylmorphine, 320,407-409 morphine 3-glucuronide, The use of 3,5-di(tert-butyl)-1,2-benzoquinone in the oxidative deammination of N-deactylcolchicine and Ndeacetylthiocolchicine has given the compounds 237a-237d, presumably via intermediates with the part-structures 234 and 235, oxidised to 236, with final oxidation of 237a to 237b and 237c to 237d. 469 Colchicine reacts with chloroethylamine to give the aziridine 238a and the tertiary base 238b, 470 and N-deacetylthiocolchicine has been converted into 239. 471 Irradiation of colchicone has given β-lumicolchicone 240, but thiocolchicone is not similarly affected.…”