The integrins α v β 3 and α v β 5 and the membrane-spanning surface protein aminopeptidase-N (APN) are highly expressed in tumor-induced angiogenesis, making them attractive targets for therapeutic intervention. Both integrins and APN recognize a broad range of peptides containing RGD (ArgGly-Asp) and NGR (Asn-Gly-Arg) motifs, respectively. Here, we describe the design, synthesis, and characterization of a series of mono-and difunctionalized platinum(IV) complexes in which a conjugated peptide motif, containing either RGD, CRGDC, (RGDfK)c or NGR, is appended as a 'tumor-homing device' to target tumor endothelial cells selectively over healthy cells. Platinum(IV)-peptide complexes with non-specific amino acids or peptide moieties were prepared as controls. Concentration-response curves of these compounds were evaluated against primary proliferating endothelial cells and tumor cell lines and compared to those of cisplatin, a well-described platinumbased chemotherapeutic agent. The Pt(IV)-RGD conjugates were highly and specifically cytotoxic to α v β 3 and α v β 5 containing cell lines, approaching the activity of cisplatin. The Pt(IV)-NGR complexes were less active than Pt(IV)-RGD-containing compounds but more active than nonspecific Pt-peptide controls. Integrin α v β 3 mediated, at least in part, the anti-proliferative effect of an Pt(IV)-RGD conjugate, as demonstrated by a decreased inhibitory response when endothelial cells were either (1) incubated with an excess of α v β 3 /α v β 3 -specific RGD pentapeptides, or (2) transfected with RNAi for β 3 , but not β 1 , integrins. These results suggest a rational approach to improved chemotherapy with Pt(IV)-peptide conjugates by selective drug delivery to the tumor compartment.

Organoactinide complexes of the type Cp* 2 AnMe 2 (An ) Th, U) have been found to be efficient catalysts for the hydroamination of terminal alkynes with aliphatic primary amines. The chemoselectivity and regioselectivity of the reactions depend strongly on the nature of the catalyst and the nature of the amine and show no major dependence on the nature of the alkyne. The hydroamination reaction of the terminal alkynes with aliphatic primary amines catalyzed by the organouranium complexes produces the corresponding imines where the amine and the alkyne are regioselectively disposed in a syn-regiochemistry, whereas for similar reactions with the organothorium complex besides the methyl alkylated imine, dimeric and trimeric alkyne oligomers are also produced. For (TMS)CtCH and EtNH 2 both organoactinides produced the same imine compounds when the reaction is carried out in THF or toluene. In benzene, both imines E and Z (TMS)CH 2 CHNdEt are obtained, the earlier undergo a 1,3-silyl Brook sigmatropic rearrangement toward the enamine, whereas the latter remains unchanged. Mechanistic studies on the hydroamination of (TMS)CtCH and EtNH 2 promoted by the organouranium complex show that the first step in the catalytic reaction is the formation of the bis(amido) complex, found in equilibrium with the corresponding bisamido-amine complex, which loses an amine, yielding a uranium-imido complex. Insertion of the alkyne into the imido bond with subsequent amine protonolysis, isomerization, and product release comprise the primary steps in the catalytic cycle. The kinetic rate law was found to follow an inverse kinetic order in amine, a first order in complex, and a zero order in alkyne, with ∆H q ) 11.7(3) kcal mol -1 , ∆S q ) -44.5(8) eu. The turnoverlimiting step is the release of an amine from the bisamido complex yielding the imido complex.The key organoactinide intermediate for the intermolecular hydroamination reaction was found to be the corresponding actinide-imido complexes. For both actinides the complexes have been characterized, and for thorium the single-crystal X-ray diffraction was studied. A plausible mechanistic scenario is proposed for the hydroamination of terminal alkynes and aliphatic primary amines.3

Organoactinide complexes of the type Cp* 2 AcR 2 (Ac ) Th, U) catalyze the intermolecular hydroamination of terminal alkynes with aliphatic amines. The regioselectivity of the products can be tuned by the alkyne and the metal. Mechanistic studies shows that the ratelimiting step is the formation of an actinide imido complex. For thorium, the imido intermediate has been characterized by standard techniques, including X-ray diffraction.