Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics.

Pyrrolo[3,2-d]pyrimidines have been studied for many years as potential lead compounds for the development of antiproliferative agents. Much of the focus has been on modifications to the pyrimidine ring, with enzymatic recognition often modulated by C2 and C4 substituents. In contrast, this work focuses on the N5 of the pyrrole ring by means of a series of novel N5-substituted pyrrolo[3,2-d]pyrimidines. The compounds were screened against the NCI-60 Human Tumor Cell Line panel, and the results were analyzed using the COMPARE algorithm to elucidate potential mechanisms of action. COMPARE analysis returned strong correlation to known DNA alkylators and groove binders, corroborating the hypothesis that these pyrrolo[3,2-d]pyrimidines act as DNA or RNA alkylators. In addition, N5 substitution reduced the EC50 against CCRF-CEM leukemia cells by up to 7-fold, indicating that this position is of interest in the development of antiproliferative lead compounds based on the pyrrolo[3,2-d]pyrimidine scaffold.

Congenital Zika syndrome: Pitfalls in the placental barrier.

Much progress with respect to congenital Zika virus (ZIKV) pathogenesis has been achieved after the 2015 outbreak in Brazil. It is now accepted that ZIKV is vertically transmitted, infects cells of the developing central nervous system and the placenta, yet it is unclear to what extent placental affection contributes to the development of congenital ZIKV. The association between fulminant villitis and severe fetal involvement emerges as a possibility. ZIKV is unique among the Flaviviruses in its ability to be sexually transmitted, possibly responsible for its teratogenicity. Furthermore, there is controversy over the participation of antibody dependent enhancement (ADE) in patients with non-neutralizing anti-Flavivirus antibodies, a phenomenon previously recognized in serious DENV infections. Our aim was to analyze information regarding the contribution of the placental barrier as an actual player in neonatal ZIKV. Therefore, we underwent a systematic review with keywords "Zika virus" and "ZIKV". Articles were screened for relevance concerning the topics of microcephaly, transplacental transmission, sexual transmission, and ADE. We identified variables that affect the severity of congenital Zika syndrome: age of gestation at maternal infection, the extent of placental disruption (villitis), sexual transmission, initial viral replication at the uterine wall, anti-DENV antibodies, and the possibility of antibody-mediated transcytosis of ZIKV through the placenta. These questions may not seem relevant when Zika becomes endemic, and we are no longer witness to the extreme clinical sequelae seen when the virus moves through an immunologically naïve population; however, characterizing the pathogenesis of congenital Zika syndrome will continue to further our understanding.