Twenty-three carbobenzoxy dipeptide esters, carbobenzoxy peptides, and dipeptides of 1-aminocyclopentanecarboxylic acid were synthesized. Rotation, Ri, and electrophoretic migrations are given. The ability to inhibit Sarcoma-180 in mice varied significantly with structure.Cycloaliphatic amino acids have been investigated for their antitumor properties by Ross,1 Connors,2 and Martel3 and their collaborators, with the finding that 1-aminocyclopentanecarboxylic acid (NSC-1026)4 (I) is effective on in mice, and on Walker (rat) Carcinoma-256. Preliminary clinical trials have been reported.5Connors, et al.,2 have evaluated the effect of substitution on the cyclopentane ring and the amino and carboxyl groups, and conclude that limited substitution markedly diminishes antitumor activity. Both C-terminal and N-terminal glycine peptides retained activity in rats, but the phenylalanyl-l-aminocyclopentanecarboxylic acid peptide was inactive.This Laboratory has been concerned with the synthesis of antibacterial and potential antitumor peptides.
Hydrolysis of the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) at the cell membrane induces the release of inositol 1,4,5-trisphosphate (IP3) into the cytoplasm and diffusion of diacylglycerol (DAG) through the membrane, respectively. Release of IP3 subsequently increases Ca2+ levels in the cytoplasm, which results in activation of protein kinase C α (PKCα) by Ca2+ and DAG, and finally the translocation of PKCα from the cytoplasm to the membrane. In this study, we developed a metabolic reaction–diffusion framework to simulate PKCα translocation via PIP2 hydrolysis in an endothelial cell. A three-dimensional cell model, divided into membrane and cytoplasm domains, was reconstructed from confocal microscopy images. The associated metabolic reactions were divided into their corresponding domain; PIP2 hydrolysis at the membrane domain resulted in DAG diffusion at the membrane domain and IP3 release into the cytoplasm domain. In the cytoplasm domain, Ca2+ was released from the endoplasmic reticulum, and IP3, Ca2+, and PKCα diffused through the cytoplasm. PKCα bound Ca2+ at, and diffused through, the cytoplasm, and was finally activated by binding with DAG at the membrane. Using our model, we analyzed IP3 and DAG dynamics, Ca2+ waves, and PKCα translocation in response to a microscopic stimulus. We found a qualitative agreement between our simulation results and our experimental results obtained by live cell imaging. Interestingly, our results suggest that PKCα translocation is dominated by DAG dynamics. This three-dimensional reaction–diffusion mathematical framework could be used to investigate the link between PKCα activation in a cell and cell function.
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