N-formimidoyl analogues of distamycin

Novel N-formimidoyl analogues of distamycin, bearing a second positive charge (3-5) or a single positive charge (6) at the N-terminus, were synthesised and assayed for their DNA affinity and anti-herpes activity

NMR-Spectroscopic, computational and mass-spectrometric investigations on the cis/trans analogues of 2,3,4-trihydronaphthalene-1-one

Abstract—NMR-Spectroscopic, computational and mass-spectrometric studies of the cis/trans isomers of N-[8-(acetylamino)-4-(2,2- dimethyl-1,1-diphenyl-silapropoxy)-6-fluoro-5-methyl-1-one-2,3,4-trihydronaphthyl]acetamide (1a and 1b), obtained as intermediates in the synthesis of an important class of alkaloid molecules, are reported. 1H and 13C NMR analyses show an unusual axial preference of the TBDPSi– (tert-butyldiphenylsilyl) group in position 4 in both the isomers. Mass spectrometric evidence demonstrates that trans isomer has a higher affinity for ammonium ions than the cis isomer and that only the ammonium adduct [1bþNH4]þ and the protonated molecule [1bþH]þ show the fragmentation in which loss of benzene is observed. Moreover, molecular mechanics and semi-empirical calculations indicate that a group of trans conformers tend to place one of the phenyl rings of the TBDPSiO– group in a offset p-stacked geometry with the compound’s aromatic ring. The combination and the detailed analyses of these experimental and theoretical results could support the p–p interaction obtained as a conformational preference in the trans isomer

Topoisomerase poisoning activity of novel disaccharide anthracyclines.

International audienceDoxorubicin and idarubicin are very effective anticancer drugs in the treatment of human hematological malignancies and solid tumors. These agents are well known topoisomerase II poisons; however, some anthracycline analogs recently have been shown to poison topoisomerase I. In the present work, we assayed novel disaccharide analogs and the parent drug, idarubicin, for their poisoning effects of human topoisomerase I and topoisomerases IIalpha and IIbeta. Drugs were evaluated with a DNA cleavage assay in vitro and with a yeast system to test whether the agents were able to poison the enzymes in vivo. We have found that the test agents are potent poisons of both topoisomerases IIalpha and IIbeta. The axial orientation of the second sugar relative to the first one of the novel disaccharide analogs was shown to be required for poisoning activity and cytotoxicity. Interestingly, idarubicin and the new analogs stimulated topoisomerase I-mediated DNA cleavage at low levels in vitro. As expected, the cytotoxic level of the drug was highly affected by the content of topoisomerase II; nevertheless, the test agents had a yeast cell-killing activity that also was weakly dependent on cellular topoisomerase I content. The results are relevant for the full understanding of the molecular mechanism of topoisomerase poisoning by anticancer drugs, and they define structural determinants of anthracyclines that may help in the rational design of new compounds directed against topoisomerase I

Clinical and Pharmacologic Study of the Novel Prodrug Delimotecan (MEN 4901/T-0128) in Patients with Solid Tumors

Purpose: To investigate i.v. administration of delimotecan (MEN 4901/T-0128), a carboxymethyldextran polymer prodrug of the active camptothecin derivative T-2513, and to assess the maximum tolerated dose, safety profile, clinical pharmacology, and antitumor activity of delimotecan and metabolites. Experimental Design: Patients with solid tumors refractory to standard therapy received i.v. delimotecan as 3-hour infusion once every 6 weeks. The starting dose was 150 mg/m(2), followed by an accelerated dose escalation with at least one patient per dose level. The pharmacokinetics of delimotecan, T-2513, and its metabolites, SN-38, SN-38G, T-1335, T-0055, and T-3921, were assessed in plasma and urine, and their pharmacodynamics were determined by measuring the effect of the treatment on hematologic and nonhematologic toxicity. Results: Twenty-two patients received 35 courses. Dose-limiting toxicities were observed at 5,400 mg/m(2) (n = 1), 3,600 mg/m(2) (n = 1), and 2,400 mg/m(2) (n = 2). The dose level of 1,800 mg/m(2) was determined as maximum tolerated dose. Two partial responses were observed in patients with anal cancer (1800 mg/m(2)) and head and neck cancer (2400 mg/m(2)). Delimotecan had a long terminal half-life of 109 h, and relatively high exposures to T-2513 and SN-38 were obtained. The percentage decrease in WBC and absolute neutrophil count significantly correlated with the dose of delimotecan. Conclusions: Based on its preliminary antitumor activity, safety profile, and pharmacokinetic profile, we recommend to evaluate delimotecan given as 3-hour infusion once every 6 weeks at a dose level of 1,800 mg/m(2) in a phase II study

Impairment of myocardial contractility by anticancer anthracyclines: role of secondary alcohol metabolites and evidence of reduced toxicity by a novel disaccharide analogue

1. The anticancer anthracycline doxorubicin (DOX) causes cardiotoxicity. Enzymatic reduction of a side chain carbonyl group converts DOX to a secondary alcohol metabolite that has been implicated in cardiotoxicity. We therefore monitored negative inotropism, assessed as inhibition of post-rest contractions, in rat right ventricle strips exposed to DOX or to analogues forming fewer amounts of their alcohol metabolites (epirubicin, EPI, and the novel disaccharide anthracycline MEN 10755). 2. Thirty μM EPI exhibited higher uptake than equimolar DOX, but formed comparable amounts of alcohol metabolite due to its resistance to carbonyl reduction. MEN 10755 exhibited also an impaired uptake, and consequently formed the lowest levels of alcohol metabolite. Accordingly, DOX and EPI inhibited post-rest contractions by ∼40 – 50%, whereas MEN 10755 inhibited by ∼6%. 3. One hundred μM EPI exhibited the same uptake as equimolar DOX, but formed ∼50% less alcohol metabolite. One hundred μM MEN 10755 still exhibited the lowest uptake, forming ∼60% less alcohol metabolite than EPI. Under these conditions DOX inhibited post-rest contractions by 88%. EPI and MEN 10755 were ∼18% (P<0.05) or ∼80% (P<0.001) less inhibitory than DOX, respectively. 4. The negative inotropism of 30 – 100 μM DOX, EPI, or MEN 10755 correlated with cellular levels of both alcohol metabolites (r=0.88, P<0.0001) and carbonyl anthracyclines (r=0.79, P<0.0001). Nonetheless, multiple comparisons showed that alcohol metabolites were ∼20 – 40 times more effective than carbonyl anthracyclines in inhibiting contractility. The negative inotropism of MEN 10755 was therefore increased by chemical procedures, like side chain valeryl esterification, that facilitated its uptake and conversion to alcohol metabolite but not its retention in a carbonyl form. 5. These results demonstrate that secondary alcohol metabolites are important mediators of cardiotoxicity. A combination of reduced uptake and limited conversion to alcohol metabolite formation might therefore render MEN 10755 more cardiac tolerable than DOX and EPI