| Autor: |
Zhidkov ME; Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia., Sidorova MA; Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia., Smirnova PA; Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia., Tryapkin OA; Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia., Kachanov AV; Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia., Kantemirov AV; Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia., Dezhenkova LG; Laboratory of Chemical Transformation of Antibiotics, Gause Institute of New Antibiotics, 119021 Moscow, Russia., Grammatikova NE; Laboratory of Chemical Transformation of Antibiotics, Gause Institute of New Antibiotics, 119021 Moscow, Russia., Isakova EB; Laboratory of Chemical Transformation of Antibiotics, Gause Institute of New Antibiotics, 119021 Moscow, Russia., Shchekotikhin AE; Laboratory of Chemical Transformation of Antibiotics, Gause Institute of New Antibiotics, 119021 Moscow, Russia., Pak MA; Department of Chemistry and Materials, Institute of High Technologies and Advanced Materials, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, Russia., Styshova ON; Departments of Biotechnology and Marine Natural Compounds Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of The Russian Academy of Sciences, 690922 Vladivostok, Russia., Klimovich AA; Departments of Biotechnology and Marine Natural Compounds Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of The Russian Academy of Sciences, 690922 Vladivostok, Russia., Popov AM; Departments of Biotechnology and Marine Natural Compounds Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of The Russian Academy of Sciences, 690922 Vladivostok, Russia. |
| Abstrakt: |
Based on the results of our own preliminary studies, the derivative of the marine alkaloid fascaplysin containing a phenyl substituent at C-9 was selected to evaluate the therapeutic potential in vivo and in vitro. It was shown that this compound has outstandingly high antimicrobial activity against Gram-positive bacteria, including antibiotic-resistant strains in vitro. The presence of a substituent at C-9 of the framework is of fundamental importance, since its replacement to neighboring positions leads to a sharp decrease in the selectivity of the antibacterial action, which indicates the presence of a specific therapeutic target in bacterial cells. On a model of the acute bacterial sepsis in mice, it was shown that the lead compound was more effective than the reference antibiotic vancomycin seven out of nine times. However, ED 50 value for 9-phenylfascaplysin ( 7 ) was similar for the unsubstituted fascaplysin ( 1 ) in vivo, despite the former being significantly more active than the latter in vitro. Similarly, assessments of the anticancer activity of compound 7 against various variants of Ehrlich carcinoma in mice demonstrated its substantial efficacy. To conduct a structure-activity relationship (SAR) analysis and searches of new candidate compounds, we synthesized a series of analogs of 9-phenylfascaplysin with varying aryl substituents. However, these modifications led to the reduced aqueous solubility of fascaplysin derivatives or caused a loss of their antibacterial activity. As a result, further research is required to explore new avenues for enhancing its pharmacokinetic characteristics, the modification of the heterocyclic framework, and optimizing of treatment regimens to harness the remarkable antimicrobial potential of fascaplysin for practical usage. |
