Synthesis and Structure−Activity Relationships of Novel 7-Substituted 1,4-Dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic Acids as Antitumor Agents. Part 1

Abstract

In an attempt to search for clinically useful antitumor agents, we have discovered that a series of 1,7-disubstituted-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids possessed moderate cytotoxic activity. We investigated the structure-activity relationships in this series of compounds by changing N-1 and C-7 positions and the core ring structure itself and evaluated the synthesized compounds against several murine and human tumor cell lines. These modifications led us to the following findings. (1) The 2-thiazolyl group at the N-1 position of the naphthyridine structure is the best substituent for antitumor activity. (2) Regarding core ring structure, the naphthyridine derivative is the most active followed by pyridopyrimidine analogue. (3) At the C-7 position, aminopyrrolidine derivatives are more effective than other amines or thioether derivatives. Finally, the trans-3-amino-4-methoxypyrrolidinyl derivative (43j) and the 3-amino-3-methylpyrrolidinyl derivative (43f) as well as 3-aminopyrrolidinyl derivative (AT-3639, 1) were determined to be effective in in vitro and in vivo antitumor assays, and their activity was comparable to that of etoposide.

Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks

“…Quinolone derivatives have recently been described as an alternative scaffold to the classic antineoplastic topoisomerase II poisons, including the anthracyclines, anthracenediones and epipodophyllotoxins [1][2][3][4][5]. These drugs are broadly used in the treatment of both solid and hematologic malignancies [6][7][8].…”

Vosaroxin: a new valuable tool with the potential to replace anthracyclines in the treatment of AML?

“…Quinolone antibiotics act by poisoning bacterial DNA gyrase and topoisomerase IV [43][44][45] and due to the structural similarities with mammalian topo II the search began for a novel 'quinolone' with cytotoxic activity [46]. Vosaroxin is a naphthyridine-derived small molecule that exists as a 'zwitterion'-containing carboxylic acid and amine functional groups [47].…”

In Vitro Antimicrobial Activity of New Substituted Phenylthiazole Derivatives

“…Due to increasing of microbial resistance towards the existing antibiotics, new chemical compounds have been synthesized by thiazole with different aromatic substituted with a wide range of biological activities such as anticancer [3][4][5], antibacterial [6], antifungal [7], anti-inflammatory [8], antitubercular [9], cardiotonic [10] and antidegenerative activity on cartilage [11] etc. Already, we synthsised Alkyl 2-(Dialkylamino)-4 phenylthiazole-5-carboxylates derivatives (6a-4l) in good yields [12].…”