The ATP-binding cassette transporter ABCG2 mediates the efflux of several chemotherapeutic drugs, contributing to the development of multidrug resistance (MDR) in many cancers. The most promising strategy to overcome ABCG2-mediated MDR is the use of specific inhibitors. Despite many efforts, the identification of new potent and specific ABCG2 inhibitors remains urgent. In this study, a structural optimization of indeno[1,2-b]indole was performed and a new generation of 18 compounds was synthesized and tested as ABCG2 inhibitors. Most compounds showed ABCG2 inhibition with IC₅₀ values below 0.5 µM. The ratio between cytotoxicity (IG₅₀) and ABCG2 inhibition potency (IC₅₀) was used to identify the best inhibitors. In addition, it was observed that some indeno[1,2-b]indole derivatives produced complete inhibition, while others only partially inhibited the transport function of ABCG2. All indeno[1,2-b]indole derivatives are not transported by ABCG2, and even the partial inhibitors are able to fully chemosensitize cancer cells overexpressing ABCG2. The high affinity of these indeno[1,2-b]indole derivatives was confirmed by the strong stimulatory effect on ABCG2 ATPase activity. These compounds did not affect the binding of conformation-sensitive antibody 5D3 binding, but stabilized the protein structure, as revealed by the thermostabilization assay. Finally, a docking study showed the indeno[1,2-b]indole derivatives share the same binding site as the substrate estrone-3-sulfate.

Ganciclovir (GCV) has been implicated in the development of testicular alterations. Exposure on gestational day (GD) 10 in rats induced permanent effects, including focal reduction or absence of germ cells (Sertoli cell-only tubules). Because the timing of exposure can be critical for testicular effects, we exposed rat dams to 300 mg/kg GCV (three 100mg/kg subcutaneous injections) on GD10, 14 and 19, when germ cells have high rates of migration, proliferation and are mitotically quiescent, respectively. Males exposed to GCV in utero on GD10 and 14 were evaluated for androgenization markers, serum and fecal androgens, and testicular histomorphometry at adulthood. Double-labelling immunofluorescence for DAZL and Ki67 were used to assess gonocytes number and the proliferative activity of germ and somatic cells in fetal testes on GD15 and 20, i.e., 24 h after GCV exposure. Adult rats exposed on GD14 showed delayed puberty onset, despite normal androgen levels. Also, there was a 50% reduction in testicular weight and about 30% of seminiferous tubules lacking germ cells. Effects on GD10 animals were less pronounced. In the fetal testis, the number of gonocytes was reduced by 50% in rats exposed on GD14, but normal in GD19 fetuses. GCV also reduced Sertoli cell proliferation immunolabelling in GD19 fetuses and Sertoli cell number in adults. In conclusion, GCV toxicity on germ cells seems to be linked to their proliferation rate and GD14 is a critical window in rats, when GCV exposure causes an acute massive loss of germ cells that persists until adulthood.

Background/Objectives:Pereskia aculeata and Pereskia grandifolia belong to the Cactaceae family, despite their foliar and woody stem characteristics. Both species are commonly known as Ora-pro-nóbis (derived from Latin, meaning “pray for us”), a name rooted in their historical use in colonial Brazil due to their nutritional value, particularly P. aculeata, which is frequently described as a high-protein food source. The goal of the present study was to compare these species based on phytochemical composition and antioxidant capacity. Methods: Both species were investigated for their chemical antioxidant properties (DPPH and phosphomolybdenum complex) and cellular anti-ROS activity using the CACO-2 cell line. A comprehensive phytochemical analysis was performed using LC-MS and GC-MS. Results: P. aculeata exhibited a more abundant content of phenolics and flavonoids, with greater structural variability in phenolic compounds and glycosylated flavonoids than P. grandifolia. Still, P. aculeata showed a more potent chemical antioxidant effect. By contrast, in P. grandifolia, a series of novel saponins was now discovered and characterized. In addition, the compounds from this species exhibited a greater cellular antioxidant activity than those of P. aculeata. Tryptophan-derived alkaloids, such as abrine (N-methyltryptophan), were present in both species, but hypaphorine only in P. aculeata. Conclusions: Both species of Pereskia exhibit potential health benefits, including distinct antioxidant activity, among other unexplored effects, given their significant variability in phytochemicals. These differences could be investigated in greater depth using combined LC-MS and GC-MS, thereby enabling more confident structural investigations of these natural compounds.