Design, synthesis and biological evaluation of novel aminopropylcarboxamide derivatives as sigma ligands. (15th September 2022)

• Record Type: Journal Article
• Authors: Zampieri, Daniele; Fortuna, Sara; Romano, Maurizio; Amata, Emanuele; Dichiara, Maria; Marrazzo, Agostino; Pasquinucci, Lorella; Turnaturi, Rita; Mamolo, Maria Grazia
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 72(2022)
• Publication Date: 2022-09-15
• Subjects: Sigma receptor -- Aminopropylcarboxamide -- Affinity -- Selectivity -- Cytotoxicity -- Molecular modelling; ADME absorption distribution metabolism excretion -- CNS central nervous system -- DAMGO selective μ-opioid agonist -- DOR δ-opioid receptor -- DTG di-o-tolylguanidine -- ER estrogen receptor -- GI gastrointestinal -- Halo Haloperidol -- HER2 tyrosine-protein kinase erb-2 -- IC50 50% of maximal cytotoxic concentration -- KOR κ-opioid receptor -- MAC-30 meningioma-associated protein-30 -- MAM mitochondrion-associated membrane -- MOR μ-opioid receptor -- NMDA N-methyl-D-aspartic acid -- NPC1 Niemann-Pick cholesterol transporter type1 -- p53 cellular tumor antigen p53 -- PR progesterone receptor -- PTZ pentazocine -- RO5 rule of five -- S1R and S2R sigma-1 receptor and sigma-2 receptor -- Srms Siramesine -- TMEM97 transmembrane protein-97 -- U50488 selective k-opioid agonist.; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128860
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: We present a new series of aminopropylcarboxamide derivatives gifted with preferential affinity for S2R subtype. The best result in terms of selectivity was reached by quinoline derivative 5e which showed a Ki S2R = 16 nM and selectivity ratio of 35. Cytotoxic evaluation revealed that the best compounds of the series possess higher level of toxicity in two cancer cell lines (MCF7 and SKBR3). Computational study confirms a strong interaction with the S2R binding site. Highlights: 8 new aminopropylcarboxamide derivatives have been designed and synthesized. 4 out of 8 compounds showed high affinity towards sigma-2 receptor subtype. Quinoline derivative 5e showed the best selectivity profile. Computational study confirms the interaction with active site of sigma-2 receptor. Compounds showed cytotoxicity against two cancer cell lines (MCF7 and SKBR3) Abstract: In our continuing effort to develop novel sigma receptor (SR) ligands, we present the design, synthesis and binding studies of a small library of aminopropylcarboxamide derivatives, obtained from a deconstruction of the piperidine ring of previously synthesized piperidine-based compounds. The best results were achieved with benzofuran (5c, 5g ) and quinoline (5a, 5e ) derivatives. These compounds revealed the highest affinity for both receptor subtypes. In particular, the 3, 4-dimethoxyphenyl derivatives 5e and 5g showed the highest selectivity profile for S2R, especially the quinoline derivative 5e exhibited a 35-fold higher affinity for S2R subtype. The cytotoxic activity of aforementioned compounds was evaluated against SKBR3 and MCF7 cell lines, widely used for breast cancer studies. Whereas the potency of 5g was similar that of Siramesine and Haloperidol in both cell lines, compounds 5a, 5c and 5e exhibited a potency at least comparable to that of Haloperidol in SKBR3 cells. A molecular modelling evaluation towards the S2R binding site, confirmed the strong interaction of compound 5e thus justifying its highest S2R affinity.