Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC50 0.62 µM) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons

The early Turolian (late Miocene) Cervidae (Artiodactyla, Mammalia) from the fossil site of Dorn-Dürkheim 1 (Germany) and implications on the origin of crown cervids

Dental and cranial appendage remains of Cervidae from the fossil site of Dorn-Dürkheim are studied in detail. The material mainly includes isolated teeth, isolated pedicles and antler pieces. Neither tooth rows nor complete appendages are recorded. Comparative morphology and statistics of morphometrics (principal component analysis and discriminant analysis) allow for the classification of small and large dentitions, small cranial appendages, two morphotypes of large pedicles and two morphotypes of large antlers. Possible combinations of the classified units document the sympatric occurrence of three species, namely, Procapreolus sp., Muntiacinae gen. and sp. indet., cf. Cervavitulus mimus, but the fragmentary condition of the material leads to ambiguity regarding their composition and, consequently, to a certain extent regarding the taxonomic identification. However, these remains indicate the contemporaneous occurrence of early Turolian members of the crown cervids Muntiacinae and Capreolinae and close a previous spatiotemporal gap in the European cervid record. In addition, their presence proves the progressive turnover from dichotomous-antlered muntiacines to early monopodial-antlered crown cervids from NE to SW Europe in the late Miocene. The taxonomical assignment challenges the recent hypothesis on the origin of crown Cervidae around the middle/late Miocene border since Dorn-Dürkheim cervids provide further evidence for the successive achievement of derived characters in cranial appendages of crown cervids (mediopostorbital position and backwards orientation of pedicles, coronet development, shaft development/elongation, beam development and increase in number of antler tines) in the lineage of crown cervids, which originated during the middle Miocene.Fil: Azanza, Beatriz. Universidad de Zaragoza. Facultad de Ciencias; EspañaFil: Rössner, Gertrud E.. Bayerische Staatssammlung Fur Palaontologie Und Geologie; AlemaniaFil: Ortiz Jaureguizar, Edgardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin