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The opportunistic human pathogen Pseudomonas aeruginosa exhibits great resistance to antibiotics; so, new therapeutic agents are urgently needed. Since polyamines levels are incremented in infected tissues, we explored whether the formation of a toxic aldehyde in polyamines degradation can be exploited in combating infection. We cloned the gene encoding the only aminoaldehyde dehydrogenase involved in P. aeruginosa polyamines‐degradation routes, PaPauC, overexpressed this enzyme, and found that it oxidizes 3‐aminopropionaldehyde (APAL) and 3‐glutamyl‐3‐aminopropionaldehyde (GluAPAL) − produced in spermine (Spm), spermidine (Spd), and diaminopropane (Dap) degradation, as well as 4‐aminobutyraldehyde (ABAL) and 4‐glutamyl‐4‐aminobutyraldehyde (GluABAL) − formed in putrescine (Put) degradation. As the catalytic efficiency of PaPauC with APAL was 30‐times lower than with GluAPAL, and GluAPAL is predominantly formed, APAL will be poorly oxidized 'in vivo'. We found polyamines‐induced increases in the PaPauC activity of cell crude‐extracts and in the expression of the PapauC gene that were diminished by glucose. Spm, Spd, or Dap, but not Put, were toxic to P. aeruginosa even in the presence of other carbon and nitrogen sources, particularly to a strain with the PapauC gene disrupted. APAL, but not GluAPAL, was highly toxic even to wild‐type cells, suggesting that its accumulation, particularly in the absence of, or low, PaPauC activity is responsible for the toxicity of Spm, Spd, and Dap. Our results shed light on the toxicity mechanism of these three polyamines and strongly support the critical role of PaPauC in this toxicity. Thus, PaPauC emerges as a novel potential drug target whose inhibition might help in combating infection by this important pathogen. [ABSTRACT FROM AUTHOR]

Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and theirin vitroantiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound9edisplayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound9ealso exhibited greater tumor selectivity than human lymphocytes.In silicoADME predictions revealed that compound9ehas the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile. [ABSTRACT FROM AUTHOR]

Two diazabicyclic analogues of ranolazine, ( S , S , S )-5 and ( S , S , R )-5, and their epimeric mixture were synthesized. Furthermore, their vasomotor effects on rat aorta rings precontracted with phenylephrine were analyzed. These compounds showed vasodilating effects significantly greater than ranolazine. The vasodilating activities of these analogues have two components, one that depends on the endothelium, due to the release of NO, and another one due to a direct effect on the vascular smooth muscle. The compounds [( S , S , S )( S , S , R )]-5 and ( S , S , R )-5 induce, in a manner similar to ranolazine, the release of a prostanoid from the cyclooxygenase pathway, whose vasoconstrictor effect is masked by the predominant vasodilation induced by these compounds. [ABSTRACT FROM AUTHOR]

The transport of electrons along photosynthetic and respiratory chains involves a series of enzymatic reactions that are coupled through redox mediators, including proteins and small molecules. The use of native and synthetic redox probes is key to understanding charge transport mechanisms and to the design of bioelectronic sensors and solar energy conversion devices. However, redox probes have limited tunability to exchange charge at the desired electrochemical potentials (energy levels) and at different protein sites. Herein, we take advantage of electrochemical scanning tunneling microscopy (ECSTM) to control the Fermi level and nanometric position of the ECSTM probe in order to study electron transport in individual photosystem I (PSI) complexes. Current-distance measurements at different potentiostatic conditions indicate that PSI supports long-distance transport that is electrochemically gated near the redox potential of P700, with current extending farther under hole injection conditions., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)