Thiosemicarbazone Derivatives Developed to Overcome COTI-2 Resistance

COTI-2 is currently being evaluated in a phase I clinical trial for the treatment of gynecological and other solid cancers. As a thiosemicarbazone, this compound contains an N,N,S-chelating moiety and is, therefore, expected to bind endogenous metal ions. However, besides zinc, the metal interaction properties of COTI-2 have not been investigated in detail so far. This is unexpected, as we have recently shown that COTI-2 forms stable ternary complexes with copper and glutathione, which renders this drug a substrate for the resistance efflux transporter ABCC1. Herein, the complex formation of COTI-2, two novel terminal N-disubstituted derivatives (COTI-NMe2 and COTI-NMeCy), and the non-substituted analogue (COTI-NH2) with iron, copper, and zinc ions was characterized in detail. Furthermore, their activities against drug-resistant cancer cells was investigated in comparison to COTI-2 and Triapine. These data revealed that, besides zinc, also iron and copper ions need to be considered to play a role in the mode of action and resistance development of these thiosemicarbazones. Moreover, we identified COTI-NMe2 as an interesting new drug candidate with improved anticancer activity and resistance profile

On eulerian subgraphs of complementary graphs

AbstractA graph G with p≥3 points, 0≤n≤p−3, is called n-Hamiltonian if the removal of any k points from G, 0≤k≤n, results in a Hamiltonian graph. This generalizes the concept of Hamiltonian graphs in as much as the 0-Hamiltonian graphs are precisely the Hamiltonian graphs. Sufficient conditions for a graph to be n-Hamiltonian are presented, including generalizations of results on Hamiltonian graphs due to Dirac, Ore, and Pósa