Synthesis, Antiproliferative Effect and In Silico LogP Prediction of BIM-23052 Analogs Containing Tyr Instead of Phe
Dancho Danalev,
Ivan Iliev,
Stefan Dobrev,
Silvia Angelova,
Stoiko Petrin,
Tatyana Dzimbova,
Elena Ivanova,
Dessislava Borisova,
Emilia Naydenova
Affiliations
Dancho Danalev
Biotechnology Department, University of Chemical Technology and Metallurgy, 8 Kliment Ohridski Blvd., 1756 Sofia, Bulgaria
Ivan Iliev
Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 25, 1113 Sofia, Bulgaria
Stefan Dobrev
Institute of Optical Materials and Technologies “Acad. J. Malinowski”, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 109, 1113 Sofia, Bulgaria
Silvia Angelova
Institute of Optical Materials and Technologies “Acad. J. Malinowski”, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 109, 1113 Sofia, Bulgaria
Stoiko Petrin
Biotechnology Department, University of Chemical Technology and Metallurgy, 8 Kliment Ohridski Blvd., 1756 Sofia, Bulgaria
Tatyana Dzimbova
Department Sport, Faculty of Public Health, Health Care and Sport, South-West University “Neofit Rilski”, 2700 Blagoevgrad, Bulgaria
Elena Ivanova
Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 25, 1113 Sofia, Bulgaria
Dessislava Borisova
Organic Chemistry Department, University of Chemical Technology and Metallurgy, 8 Kliment Ohridski Blvd., 1756 Sofia, Bulgaria
Emilia Naydenova
Organic Chemistry Department, University of Chemical Technology and Metallurgy, 8 Kliment Ohridski Blvd., 1756 Sofia, Bulgaria
(1) Background: Hydrophobicity (or lipophilicity) is a limiting factor in the ability of molecules to pass through cell membranes and to perform their function. The ability to efficiently access cytosol is especially important when a synthetic compound has the potential to become a drug substance. D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2 (BIM-23052) is a linear analog of somatostatin with established in vitro GH-inhibitory activity in nanomolar (nm) concentrations and high affinity to different somatostatin receptors. (2) Methods: Series of analogs of BIM-23052 were synthesized where Phe residue(s) in the BIM-23052 molecule were replaced with Tyr using standard SPPS, Fmoc/t-Bu strategy. Analyses of target compounds were performed using HPLC/MS technique. Toxicity and antiproliferative activity were studied using in vitro NRU and MTT assays. The values of logP (partition coefficient in octanol/water) for BIM-23052 and its analogs were calculated. (3) Results: The obtained data show the best antiproliferative effect against studied cancer cells for compound D-Phe-Phe-Phe-D-Trp-Lys-Thr-Tyr7-Thr-NH2 (DD8), the most lipophilic compound according to the predicted logP values. (4) Conclusions: Multiple analyses of the obtained data reveal that compound D-Phe-Phe-Phe-D-Trp-Lys-Thr-Tyr7-Thr-NH2 (DD8) where one Phe is replaced by Tyr has the best combination of cytotoxicity, antiproliferative effect and hydrolytic stability.
