Synthetic analogues of netropsin and distamycin--synthesis of a new pyridine and carbocyclic analogues of the pyrrolecarboxamide antitumour antibiotics.

Abstract

A new series of pyridine-containing analogues III-XXII of distamycin A and netrop sin was investigated by the molecular mechanics technique and molecular modelling. A pyridine analogue of netropsin (VII) is described, the first compound based on molecular studies, and two carbocyclic analogues of distamycin A with an N-terminal chloro- or bromoacetyl group (VIa, VIIa) were synthesized, as well as carbocyclic analogues of netropsin (VIIIb, Xb), potential carriers of alkylating elements. The potential use of VIa, VII, VIIa, VIIIb and Xb as carriers to place into the minor groove of DNA chemical groups capable of modifying DNA, is discussed.

New Solid Phase Synthesis of Distamycin Analogues

“…The advantage of exchange of the amidinium moiety (normally presented in distamycin) by the dimethylamino group was described earlier [ 32 ]. The compounds containing a modified terminus are chemically stable, not hygroscopic and are easy to handle.…”

New carbocyclic analogues of netropsin: synthesis and inhibition of topoisomerases.

“…2 and 3. The required starting materials I, VII, VIII and IX were prepared according to the methods worked out in our laboratory for compound 2 [6], and 5 [7] from 2-hydroxy-5-phenylazobenzoic acid, obtained by the method described by Polaczkowa [8]. The synthesis and complete physicochemical characterisation of the designed compounds will be reported elsewhere.…”

Molecular modelling of the interaction of carbocyclic analogues of netropsin and distamycin with d(CGCGAATTCGCG)2.

“…It has been found that a sequence-specific ligand binding to a longer specificity region of DNA is best obtained by connecting two netropsins or their analogues together via a short con-necting chemical group or linker [8,9]. Alternatively, we can develop the strategy that consists in replacing the N-methylpyrrole rings with new subunits of an appropriate repeat length that permits to retain the attractive features of netropsin and distamycin [8,10]. We focused on the strategy that consists in replacing the N-methylpyrrole rings with carbocyclic rings with a minor modification of cationic heads (Fig.…”

“…2). Carbocyclic analogues of netropsin and distamycin are readily available, can be modified easily, and are stable under most experimental conditions [10][11][12]. Recently, compounds 1-4 which were investigated on the standard cell line of mammalian tumour MCF-7, revealed high antitumour activity [12].…”