COTI-2
is a novel anticancer thiosemicarbazone in phase I clinical
trial. However, the effects of metal complexation (a main characteristic
of thiosemicarbazones) and acquired resistance mechanisms are widely
unknown. Therefore, in this study, the copper and iron complexes of
COTI-2 were synthesized and evaluated for their anticancer activity
and impact on drug resistance in comparison to metal-free thiosemicarbazones.
Investigations using Triapine-resistant SW480/Tria and newly established
COTI-2-resistant SW480/Coti cells revealed distinct structure–activity
relationships. SW480/Coti cells were found to overexpress ABCC1, and
COTI-2 being a substrate for this efflux pump. This was unexpected,
as ABCC1 has strong selectivity for glutathione adducts. The recognition
by ABCC1 could be explained by the reduction kinetics of a ternary
Cu-COTI-2 complex with glutathione. Thus, only thiosemicarbazones
forming stable, nonreducible copper(II)-glutathione adducts are recognized
and, in turn, effluxed by ABCC1. This reveals a crucial connection
between copper complex chemistry, glutathione interaction, and the
resistance profile of clinically relevant thiosemicarbazones.
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.
We describe herein an efficient and diastereoselective substrate-directable Heck-Matsuda reaction with nonactivated five-membered olefins. The carbamate acts as the main directing group in the arylation process allowing the synthesis of several functionalized aryl cyclopentenes in good to excellent diastereoselectivities (>85:15) and in isolated yields ranging from 41 to 90%. No double bond isomerizations were observed in these Heck reactions, and the newly created benzylic centers were preserved in all cases examined. The substrate directable Heck arylation approach was successfully applied in a straightforward total synthesis of the sphingosine 1-phosphate receptor-subtype 1 (S1P(1)) agonist VPC01091 by a concise and practical route involving 5 steps in 40% overall yield.
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