Simple route to ferrocenylalkyl nucleobases. Antitumor activity in vivo

Abstract

Ferrocenylalkyl nucleobases (1-14) were prepared via the reaction of the α-(hydroxy)alkyl ferrocenes FcCHR(OH) (Fc = ferrocenyl; R = H, Me, Et, Ph) with thymine, cytosine, iodo-cytosine and adenine in DMSO at 100• C, yields being 50-80%. The antitumor activities of ferrocenylmethyl thymine (1) against solid tumor models, carcinoma 755 (Ca755) and Lewis lung carcinoma (LLC) were studied in vivo. Therapeutic synergism of antitumor activity against LLC was demonstrated in the case of combined application of compound 1 with anticancer drug cyclophosphamide.

Ferrocene‐modified thiopyrimidines: synthesis, enantiomeric resolution, antitumor activity

“…At the same time at higher doses, 1.0 and 5.0 mg kg −1 , the effects of ferrocene were significantly lower. Such an inverse dose-effect response was found for ferrocenylmethyl benzimidazole [3b] (Lewis lung carcinoma, dose 5.0 mg kg −1 , tumor growth inhibition 70%), o-carboxybenzoylferrocene sodium salt [3d] (carcinoma 755, dose 2.5 mg kg −1 , tumor growth inhibition 70%), feroocenylmethyl thymine [10] (carcinoma 755, dose 2.5 mg kg −1 , tumor growth inhibition 70%) and the other ferrocene derivatives. [3a] The anomalies in dose-effect response may be connected to the increased immunogenicity of the ferrocene derivatives.…”

“…[13] Recently therapeutic synergism of the antitumor activity of a combination of ferrocenylmethyl thymine with the wellknown antitumor drug cyclophosphamide against Ca755 was demonstrated. [10] All these results are important for the further investigation of ferrocene compounds as prospective drugs for antitumor polychemotherapy.…”

“…Moreover, the antitumor activities of ferrocenecontaining compounds themselves were extensively studied in vitro and in vivo. [3,6 -9] It was demonstrated in experiments in vivo that ferrocene compounds with heterocyclic systems are effective against some solid tumors in mice [3,10] and human tumors. [3c] Ferricenium salts, besides their antiproliferative activity, [11] also display DNA-cleaving activity [12] and DNA synthesis inhibitory effect.…”

“…[10] In this paper we report an approach to thio-derivatives of pyrimidine ferrocenes (6a-d to 9a-d, Scheme 1). Ferrocenecontaining enantiomers with central chirality were resolved using HPLC on modified cellulose as chiral selector.…”

Macromolecular Co-Conjugates of Methotrexate and Ferrocene in the Chemotherapy of Cancer

“…The two drug systems operate by different cell killing mechanisms [1,[4][5][6], and it was of interest here to establish potentiating or additive effects [3], if any, in subsequent bio-evaluation work [2]. The conjugation was achieved by amide bond formation, resulting from reaction of drug-connected carboxylic acid function of the drugs with amine function of the carriers.…”