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The potential of structurally new ferrocene-functionalized guanidines as redox-active precursors for the synthesis of heterometallic platinum(II)−guanidine complexes with anticancer activity was studied. To this end, an atom-economical catalytic approach was followed by using ZnEt 2 to catalyze the addition of aminoferrocene and 4-ferrocenylaniline to N,N′-diisopropylcarbodiimide. Furthermore, reaction of a platinum(II) source with the newly obtained guanidines Fc−NC(NH i Pr) 2 (3) and Fc(1,4-C 6 H 4 )−NC(NH i Pr) 2 (4) provided access to the heterometallic complexes [PtCl 2 {Fc−NC(NH i Pr) 2 }(DMSO)] (5), [PtCl 2 {Fc(1,4-C 6 H 4 )−NC(NH i Pr) 2 }(DMSO)] (6), and [PtCl 2 {Fc-(1,4-C 6 H 4 )−NC(NH i Pr) 2 } 2 ] (7). Electrochemical studies evidence the remarkable electronic effect played by the direct attachment of the guanidine group to the ferrocene moiety in 3, making its one-electron oxidation extremely easy. Guanidinebased Fe−Pt complexes 5 and 6 are active against all human cancer cell lines tested, with GI 50 values in the range 1.4−2.6 μM, and are more cytotoxic than cisplatin in the resistant T-47D and WiDr cell lines.

A series of sp 2 -iminosugar-type glycomimetics bearing S-linked pseudoglycoside substituents (sulfide, sulfoxide and sulfone derivatives) has been synthesized and evaluated as new potential drugs against the protozoan parasite Leishmania, responsible of leishmaniasis, the second most relevant parasitic disease after malaria. All the prepared compounds share a bicyclic 5N,6O-oxomethylidenenojirimycin glyconelike moiety bearing a substitution pattern of configurational complementarity with the natural a-glucosides and incorporate either an n-octyl or n-dodecyl aglycone-like substituent. Not surprisingly, they behaved as potent to moderate competitive inhibitors of a-glucosidase (inhibition constants, K i , in the range 1.3 to 447 mM). Evaluation of the antileishmanial activity indicated that the dodecyl pseudoglycosides present a significant antiparasitic activity in intracellular amastigotes of Leishmania donovani, the clinically relevant form of the parasite. The antileishmanial effect seems to be associated with the anticancer and proapoptotic activity of the glycomimetics, but not with the a-glucosidase inhibitory efficiency. The (S S )-configured dodecylsulfoxide derivative 4, exhibiting the most favourable activity/toxicity profile, was further assayed in combination treatment with miltefosine, the first oral antileishmanial drug, using the fixed ratio isobologram method. The interaction between derivative 4 and 0.1, 0.2 and 0.3 mM miltefosine was classified as synergistic, showing combination indices of 0.78, 0.76 and 0.80, respectively. Additionally, a miltefosine resistant Leishmania line and the wild-type strain showed similar susceptibility to derivative 4. The results illustrate the potential of sp 2 -iminosugar pseudoglycosides as promising prototypes for the development of new therapeutic strategies for leishmaniasis. † Electronic supplementary information (ESI) available: General procedure for the glycosidase inhibition assay, Lineweaver-Burk and double reciprocal analysis plots of 2a, 5, 7, 8, full experimental data for compounds 13b, 2b and copies of the 1 H and 13 C NMR spectra of all new compounds. See

Starting from natural steroids (diosgenin, hecogenin, smilagenin, estrone), we have prepared a wide panel of selenoderivatives, including benzoselenazolones, selenosemicarbazones, isoselenocyanates, selenoureas, selenocyanates and diselenides, with the aim of developing new families of potential chemotherapeutic agents. The modification of the organoselenium moieties, and their position on the steroid provided valuable information concerning the antiproliferative activities. Among all the families accessed herein, the best profile was achieved for selenoureas on the A ring of estrone, which exhibited GI values in the range 2.0-4.1 μM for all the tested tumor cell lines, with increased potency compared with commonly used chemotherapeutic agents, like 5-fluorouracil and cisplatin. Cell cycle analysis revealed that selenoureas induced accumulation of cells in the G phase of the cell cycle in the breast cancer cell lines HBL-100 and T-47D; therefore, a different mechanism than cisplatin, that induces cell cycle accumulation in the S phase as a result of DNA damage, must be involved. In the rest of the tumor cells, a slight increase of the S compartment was observed. Moreover, selenosteoids turned out to be excellent glutathione peroxidase (GPx) mimics for the catalytic removal of deleterious HO (t 8.0-22.5 min) and alkyl peroxides (t 23.0-38.9 min) when used in substoichiometric amounts (1% molar ratio), thus providing a valuable tool for reducing the intrinsic oxidative stress in tumor progression.