Naphthylnitrobutadienes as pharmacologically active molecules: evaluation of the in vivo antitumour activity

Abstract

On the basis of our previous interesting results in vitro on the antiproliferative activity of (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1-Naph-DNB) we have designed and synthesized the new molecule methyl (2Z,4E)-2-methylsulphanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (1-Naph-NMCB) characterized by the same naphthylnitrobutadiene array but with a different functional group at one end of the diene system. This new molecule showed an in vitro antiproliferative activity more significant than that found for the original 1-Naph-DNB. In order to verify in vivo our in vitro results we have tested the antitumour activity of 1-Naph-DNB and 1-Naph-NMCB in several murine tumour models, namely the myelomonocytic P388 and the Lewis lung carcinoma 3LL in BDF1 mice, the melanoma B16 in C57Bl mice, the fibrosarcoma WEHI 164 in nude mice and, finally, the C51 colon cancer in Balb/c mice. In the case of 1-Naph-NMCB the analysis of the antitumour activity has been preceded by toxicological experiments on CD-1 mice, in order to determine the lethal (LD) and the maximal tolerated (MTD) doses together with the spectrum of histological alterations caused by its iv administration. The results obtained show that the modification of the original structure of 1-Naph-DNB according to the molecular-simplification strategy has led to an asymmetric nitrobutadiene array, i.e. that of 1-Naph-NMCB, endowed with an antitumour activity which is in some cases even better than that showed by the parental compound itself, together with differences in tumour selectivity and negligible histological toxic effects.A promising, versatile route to new, more active and/or safe nitrobutadiene derivatives has thus been positively tested.

Synthesis and Biological Evaluation of S-Substituted Perhalo-2-nitrobuta-1,3-dienes as Novel Xanthine Oxidase, Tyrosinase, Elastase, and Neuraminidase Inhibitors

“…Nitro and sulfoxide compounds have many biological activities such as antiulcer, antibacterial, antifungal, anticancer, and antihypertensive activities [10][11][12][13][14][15][16][27][28][29]. However, antixanthine oxidase, antityrosinase, antielastase, and antineuraminidase activities of these compounds have not been investigated until now.…”

“…S-, N-, N,S-substituted polyhalonitrobutadiene compounds obtained by the reactions of polyhalonitrobutadiene compounds with various nucleophilic reagents such as thiols, dithiols, and amines are given in the literature [1][2][3][4][5][6][7][8][9]. There are studies on antifungal, antibacterial, anticancer, and anti-HIV properties of these compounds [10][11][12][13][14][15][16]. Moreover, there are patents about the properties of these substances [17][18][19].…”

A Nitrocarbazole as a New Microtubule-Targeting Agent in Breast Cancer Treatment

“…Evaluation of the anticancer activity of compounds 1-8 follows a long-standing engagement by the Genoa research group in the synthesis of pharmacologically active nitroderivatives from the initial ring-opening of nitrothiophenes 9 [36][37][38][39][40][41][42][43][44], an effort that has resulted in a number of positive results in both in vitro and in vivo experiments. For instance, appreciable antitumor activity has been found for either some modified 13 [36,[38][39][40][41][42] or some selected 14 [36,37,39,40,42]; furthermore, α-glucosidase inhibition [43] or antibacterial activity [44] has, on the one hand, exhibited in nitroheterocycles obtained from our nitrobutadiene building-blocks. On the other hand, the Cosenza research group has, in turn, recently highlighted the efficacy of a nitrocarbazole as an anti-HIV agent [11].…”

ChemInform Abstract: Versatile Nitrobutadienic Building Blocks from the Ring‐Opening of 2‐ and 3‐Nitrothiophenes

“…Recently, following a preliminary screening of a number of 1,4-diaryl-2,3-dinitrobutadienes 5, the 1,4-bis(1-naphthyl) derivative 5a (Figure 2) has revealed significant pharmacological properties against tumour cell lines characterized by different mechanisms of resistance towards the most common anticancer drugs. [31][32][33][34][35] The encouraging results obtained both in vitro 31,32 and in vivo 33,34 as well as on its toxicological effects 35 have suggested 5a as a potential lead compound for a new class of pharmacologically-active molecules. On this ground, more recently some new derivatives, characterized by a common nitrobutadienic array, have been designed, synthesized and subjected to pharmacological tests.…”