Synthesis and biological activity of novel statine derivatives containing ferrocenyl moiety

Abstract

Na busca por novos inibidores de protease aspartica, conjugados de ferroceno com estatina foram planejados e sintetizados através de reação de aclopamento usando o protocolo padrão N,N'-diciclohexilcarboimida (DCC) e 1-hidroxibenzotrizol (HOBt). Os novos compostos foram caracterizados por espectroscopia de IR, 1 H NMR, MS e análise elementar. Os resultados do bioensaio mostraram que alguns dos novos compostos podem servir como ponto de partida.In a search for new aspartic protease inhibitors, conjugates of ferrocene with statine were designed and synthesized by coupling reaction using the standard N,N'-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) protocol. The title compounds were characterized by IR, 1 H NMR spectroscopy, MS and elemental analysis. The results of bioassay showed that some title compounds could serve as a starting point.Keywords: statine, ferrocene, aspartic protease, synthesis, biological activity IntroductionAspartic proteases are involved in many biological pathways in fungi, plants, humans, parasites, retroviruses. 1-2Aspergillus oryzae aspartic proteinase is found to have activity not only for the activation of trypsinogen but also for the activation of chimotrypsinogen with the cleavage of the Arg15-Ile16 bond.3 Statine, the (3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid configurational isomer is a key component of pepstatin and of other synthetic peptide inhibitors of aspartic protease. 4 It is well known that long-chain peptides can exhibit poor penetration and are generally unsuitable for a metabolically stable drug, because of enzymatic degradation.5 In many case, this inconvenience can be circumvented by shortening the length of the inhibitors.Ferrocene is a member of a special organometallic group known as metallocenes or "sandwich" molecules. Among metallocenes there are compounds with antiproliferative effect, antibiotics, and inhibitors of enzymes.6-9 Conjugates of ferrocene with well-known drugs were reported. 10-11Ferrocene-containing compounds often possess unexpected biological activity. 12 We report here the search for shorter aspartic protease inhibitors resulting from introducing ferrocenyl unit into statine and synthesized the novel statine derivatives which might provide interesting biological properties. The structure of target compounds is listed in Table 1. Experimental Materials and equipmentAll the reactions were carried out under a nitrogen atmosphere with the exclusion of moisture. All the amino acids used were L-amino acids. N-Boc-statine and N-Boc-AHPPA were synthesized according to the method described in the literature. 13 Ferrocenylmethylamine was synthesized by the literature method of Kelly et al.14 For syntheses of compounds 4 and 10 see reference.15 Solvents were purified and dried by standard methods. The melting points were determined on an XT-4 micro melting point apparatus and uncorrected. IR spectra were recorded on an EQUINOX-55 spectrometer on a KBr matrix.1 H NMR spectra were recorded on an INOVA-400 NMR spectrometer using T...

Novel Synthetic Route to α‐Aminophosphonates Containing Benzothiazole Moiety

“…The mass spectrum displayed the molecular ion [M＋Na] ＋ peak at m/z 507. All of the nonequivalent carbon atoms were identified in 13 C NMR and the total number of protons calculated from the integration curve accorded (in 1 H NMR) with the assigned structures.…”

“…The characteristic bands of the ferrocenyl group in the infrared spectrum of the compound appear at 3089, 1443 and 751 cm -1 . [13] The 1 H NMR spectrum of compound 7 exhibited a multiplet at δ 7.11-7.64, which accounts for the aromatic protons of the benzothiazole ring; a doublet appeared at δ 5.44, which accounts for CH proton; a mul-tiplet appeared at δ 3.92-4.42, which accounts for the CH 2 and ferrocenyl protons. The two ethoxys of the phosphonates are magnetically nonequivalent, which is caused by the different shielding effects of α-ferrocenyl on the two ethoxy groups.…”