N–Acyl–3,5–bis(arylidene)-4-piperidones and related compounds which stimulate fyn kinase

Abstract

This study is part of a long term project designed to explore the hypothesis that stimulation of cancer cells followed by treatment with one or more cytotoxic agents may create greater damage to tumours than to the corresponding normal tissues. The aim of the present investigation was to discover various compounds which stimulate a protein tyrosine kinase, namely fyn kinase. The N-acyl-3,5-bis(arylidene)-4-piperidones and related analogues activated this enzyme using concentrations of 25 mM while representative molecules achieved this result at 0.1 mM. Molecular modelling suggested that the compounds interact transiently with the ATP binding site of fyn kinase thereby enhancing the catalytic phosphorylation of proteins. In the future, candidate antineoplastic agents will be designed which incorporate the structural features of these enzyme stimulators with the goal of their being formed in vitro and in vivo prior to the release of cytotoxins.

1,5-Diaryl-3-oxo-1,4-pentadienes: A Case for Antineoplastics with Multiple Targets

“…Fyn kinase is a PK and is overexpressed in certain tumours [93]. The 4-piperidone 5 stimulates fyn kinase, albeit weakly, namely approximately 15% using the concentration range of 25-100 μM [94]. However conversion of 5 to various N-acyl analogues led to compounds with increased enzyme-stimulating properties, e.g., 15 caused a 56% increase in fyn kinase activity at a concentration of 0.1 nM [94].…”

“…The 4-piperidone 5 stimulates fyn kinase, albeit weakly, namely approximately 15% using the concentration range of 25-100 μM [94]. However conversion of 5 to various N-acyl analogues led to compounds with increased enzyme-stimulating properties, e.g., 15 caused a 56% increase in fyn kinase activity at a concentration of 0.1 nM [94]. In addition, this compound is a cytotoxin having an average IC 50 value of 5.11 μM in the Molt 4/C8, CEM and L1210 screens [30].…”

CoMFA and CoMSIA Studies on 1,3-Bis(benzylidene)-3,4-dihydro-1H-naphthalen-2-one, 2,6-Bis(benzylidene)cyclohexanone, and 3,5-Bis(benzylidene)-4-piperidone Series of Cytotoxic Compounds

“…10 In addition, apoptosis in human HepG2 liver cancer cells was observed by an N-acyl analog of a 3,5-bis(arylidene)-4-piperidone 11 and a substituted 1,3-bis(benzylidene)-3,4-dihydro-1H-napththalen-2-one. 12 Various 3,5-bis(benzylidene)-4-piperidones and related compounds are potent stimulators of fyn kinase 13 and weakly inhibit human N-myristoyltranferase. 14 Third, support for a markedly divergent mode of action than contemporary anticancer drugs was obtained when tumors which were resistant to a number of anticancer drugs, including the alkylating agent melphalan, were virtually free from cross resistance to various Mannich bases of R,βunsaturated ketones.…”

Σύνθεση Και Φαρμακοχημική Μελέτη Ετεροκυκλικών Ενώσεων (Χαλκονών Και Παραγώγων) Με Πιθανή Αντιφλεγμονώδη, Αντιοξειδωτική, Αντικαρκινική Δράση

“…Συμπεριφέρονται ως δέκτες Michael [276 ]και διατηρούν τη χαρακτηριστική ιδιότητα της κουρκουμίνης δηλαδή να αλληλεπιδρούν με ποικίλους μοριακούς στόχους [292]. Ενεργοποιούν τις κασπάσες -3, -8 και -9 [293], αναστέλλουν τον NF-κΒ και ρυθμίζουν την κινάση Fyn [294]. Επίσης εμφανίζουν αντιική δράση έναντι του ιού των ανθρωπίνων θηλωμάτων (HPV) αναστέλλοντας το πρωτεάσωμα [295] και διαθέτουν αντιοξειδωτικές ιδιότητες [284,296].…”