Functionalized Derivatives of 2-azaspiro[3.3]heptane-1-carboxylic Acid and 7-oxa-2-azaspiro[3.5]nonane-1-carboxylic Acid for Drug Design

2-azaspiro[3.3]heptane-1-carboxylic acid and 7-oxa-2-azaspiro[3.5]nonane-1-carboxylic acid, which had been reported as bioisoster of well-known pipecolic acid, were subjected to chemical transformations, resulting in a number of functionalized derivatives. The obtained molecules contained diversified functional groups, allowing their incorporation in bioactive compounds in versatile modes. Described synthetic approaches afforded multigram-scaled synthesis of the desired compounds with good yields, thus being applicable in drug desig

The Effect of OPA1 on Mitochondrial Ca2+ Signaling

The dynamin-related GTPase protein OPA1, localized in the intermembrane space and tethered to the inner membrane of mitochondria, participates in the fusion of these organelles. Its mutation is the most prevalent cause of Autosomal Dominant Optic Atrophy. OPA1 controls the diameter of the junctions between the boundary part of the inner membrane and the membrane of cristae and reduces the diffusibility of cytochrome c through these junctions. We postulated that if significant Ca2+ uptake into the matrix occurs from the lumen of the cristae, reduced expression of OPA1 would increase the access of Ca2+ to the transporters in the crista membrane and thus would enhance Ca2+ uptake. In intact H295R adrenocortical and HeLa cells cytosolic Ca2+ signals evoked with K+ and histamine, respectively, were transferred into the mitochondria. The rate and amplitude of mitochondrial [Ca2+] rise (followed with confocal laser scanning microscopy and FRET measurements with fluorescent wide-field microscopy) were increased after knockdown of OPA1, as compared with cells transfected with control RNA or mitofusin1 siRNA. Ca2+ uptake was enhanced despite reduced mitochondrial membrane potential. In permeabilized cells the rate of Ca2+ uptake by depolarized mitochondria was also increased in OPA1-silenced cells. The participation of Na+/Ca2+ and Ca2+/H+ antiporters in this transport process is indicated by pharmacological data. Altogether, our observations reveal the significance of OPA1 in the control of mitochondrial Ca2+ metabolism

Bicyclic Bioisosteres of Piperidine: Version 2.0

1-Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically in vivo as a new generation of saturated piperidine bioisosteres

Studying mitochondrial Ca2+ uptake – A revisit

► Mitochondrial Ca2+ sequestration was tested by various techniques. ► Kinetics and Ca2+ sensitivity of mitochondrial Ca2+ uptake depends on the techniques chosen. ► By electrophysiology, 2 and 3 distinct Ca2+ inward currents were measured in HeLa and endothelial cell mitoplasts. ► Mitoplast Ca2+ inward currents differ in frequency of appearance and conductance ranging from 7.6 to 74.3 pS. ► Mitochondrial Ca2+ uptake routes/modes exists and might be cell specific

Calcium influx pathways in breast cancer: opportunities for pharmacological intervention

Ca2+ influx through Ca2+ permeable ion channels is a key trigger and regulator of a diverse set of cellular events, such as neurotransmitter release and muscle contraction. Ca2+ influx is also a regulator of processes relevant to cancer, including cellular proliferation and migration. This review focuses on calcium influx in breast cancer cells as well as the potential for pharmacological modulators of specific Ca2+ influx channels to represent future agents for breast cancer therapy. Altered expression of specific calcium permeable ion channels is present in some breast cancers. In some cases, such changes can be related to breast cancer subtype and even prognosis. In vitro and in vivo models have now helped identify specific Ca2+ channels that play important roles in the proliferation and invasiveness of breast cancer cells. However, some aspects of our understanding of Ca2+ influx in breast cancer still require further study. These include identifying the mechanisms responsible for altered expression and the most effective therapeutic strategy to target breast cancer cells through specific Ca2+ channels. The role of Ca2+ influx in processes beyond breast cancer cell proliferation and migration should become the focus of studies in the next decade