Synthesis of 2,2'-Bis(3,6,9-triazanonyl)-4,4'-bithiazole and Related Compounds as New DNA Cleavage Agents

Abstract

Recently, the synthesis and properties of many metal complexes of amines and cyclic amines used as DNA cleavage agents have been reported. [1][2][3][4] These compounds generally contain heterocycles or polycyclic aromatic rings tethered to one or more aminoalkyl side chains, and are complexed with transition metals known to play important roles in DNA cleavage reactions. Many studies on the role of 2,4Ј-bithiazole, which constitutes a part of the C-terminus of Bleomycin, a naturally occurring anticancer agent, have also been reported. 5-7) Previously, we reported the synthesis and metal-dependent DNA cleavage activities of 4,4Ј-bithiazoles (1a, b) linked to two aminoalkyl groups at the side chain, [8][9][10] since the synthesis of substituted 4,4Ј-bithiazoles is simpler than the synthesis of 2,4Ј-bithiazoles. Our studies on these 4,4Ј-bithiazole derivatives demonstrated that 2,2Ј-bis(2-aminoethyl)-4,4Ј-bithiazole (1b) could cleave DNA under physiological conditions only in the presence of Co(II), and that DNA cleavage efficiently progressed in the absence of reductants, oxygen and light.9) It was also found that DNA cleavage by 2,2Ј-bis(aminomethyl)-4,4Ј-bithiazole (1a) required Cu(II) ions whereas 2,2Ј-bis(3-aminopropyl)-4,4Ј-bithiazole (1c) could not cleave DNA in the presence of any metal. 8,9) We also showed that 2,2Ј-bis(3,6-diazahexyl)-and 2,2Ј-bis(3,7-diazaheptyl)-4,4Ј-bithiazoles (2a, b) with additional aminoalkyl groups substituted on the amino group of each side chain of 1b did not initiate detectable DNA cleavage in the presence of Co(II) at pH 7.0 after half an hour of incubation.11) These results showed that the structure of the aminoalkyl side chains of the 4,4Ј-bithiazles determined the metal selectivity and DNA cleavage activities of these bithiazoles (1, 2). However, Stewart demonstrated that naturally occurred polyamines such as spermine, spermidine, putrescine and their derivatives strongly bind double-stranded DNA.12) Moreover, several authors have reported that many compound containing polyaminoalkyl moieties, such as spermine, spermidine and ethylenediamine, interact efficiently with DNA. 13,14) These studies prompted us to synthesize new 4,4Ј-bihiazoles substituted with polyaminoalkyl groups at each side chain, and to expect that these new compounds would interact efficiently with DNA and exhibit enhanced DNA cleavage activity. We report herein the synthesis, affinities for double-stranded DNA, and plasmid DNA cleavage abilities of new 4,4Ј-bithiazole derivatives (3). These new compounds possess longer side chains, such as 3,6,9-triazanonyl-and 3,7,11-triazaundecyl groups, than those of 1 and 2, as shown in Fig. 1. Furthermore, bithiazole derivatives (4), used as reference compounds for 3a were prepared by acylating the amino groups of 1b and 2a with amino acids. This derivatization was conducted in order to elucidate the role of the amino groups at the 3-and 6-positions of the side chains of 3a in binding to and cleaving double-stranded DNA. The structural features of the 4,4Ј-bithiazole ...

Self-activating nuclease and anticancer activities of copper(ii) complexes with aryl-modified 2,6-di(thiazol-2-yl)pyridine

“…27,28 The title Cu(II) complexes, [Cu(PDTP) Cl 2 ] (PDTP = 4-phenyl-2,6-di(thiazole-2-yl)pyridine, CuPDTP), [Cu(ADTP) Cl 2 ] (ADTP = 4-(anthracen-9-yl)-2,6-di(thiazole-2-yl)pyridine, CuADTP) and [Cu(BFDTP) Cl 2 ] (BFDTP = 4-(benzofuran-2-yl)-2,6-di(thiazole-2-yl)pyridine, CuBFDTP), were inspired by BLM and are similar to other thiazole-containing synthetic DNA nucleases. 29,30 Coordinated to the copper, the thiazole ligands were designed and synthesized to be applicable in the study of self-activating nuclease activity. Considering that the majority of the current copper complexes must be initiated by an excess of exogenous agents to cleave DNA, the present work is the first example of thiazole ligandcontaining copper complexes that exhibit self-activating oxidative cleavage.…”

An Overview of the Synthesis and Antimicrobial, Antiprotozoal, and Antitumor Activity of Thiazole and Bisthiazole Derivatives

“…Scheme 16. Synthesis of 2,2'-bisthiazole starting from 2-bromothiazole.The synthesis of symmetrical 4,4'-bisthiazole derivatives is most often performed by a condensation reaction of thioamides with 1,4-dibromo-2,3-butanedione, in a molar ratio of 2:1, in ethanol at reflux (Scheme 17)[82,83].…”