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Villa San Pietro, Italy

Loriga G.,Istituto di Farmacologia Traslazionale | Lazzari P.,Neuroscienze PharmaNess S.c.a R.l. | Lazzari P.,University of Sassari | Lazzari P.,KemoTech S.r.l. | And 9 more authors.
European Journal of Medicinal Chemistry | Year: 2013

Considering the interesting pharmacological profile of the delta (δ) selective opioid agonist compound SNC-80, conformationally constrained analogs containing two diazatricyclodecane ring systems in place of dimethylpiperazine core motif were synthesized. The compounds showed subnanomolar or low nanomolar δ opioid receptor binding affinity. Depending upon the substituents on the diazatricyclodecane ring, these compounds displayed varying selectivity for δ opioid receptor over μ and κ receptors. Amongst the novel compounds, 1Aa showed the more interesting biological profile, with higher δ affinity and selectivity compared to SNC-80. The δ receptor agonist profile and antinociceptive activity of 1Aa were confirmed using ex-vivo (isolated mouse vas deferens) and in vivo (tail flick) assays. © 2013 Elsevier Masson SAS. All rights reserved.

Shankar P.S.,Polytechnic of Milan | Bigotti S.,Polytechnic of Milan | Lazzari P.,KemoTech S.r.l. | Lazzari P.,University of Sassari | And 6 more authors.
Tetrahedron Letters | Year: 2013

Tubulysins are potent anti-mitotic natural compounds and a scalable and efficient synthetic route for generation of its analogues has been developed and extended to the synthesis of diastereoisomers and N-terminal analogues of tubulysin-U. Structure-activity-relationship studies on these synthetic analogues reaffirmed the significance of native stereochemistry of tubulysins for optimal biological activity and cytotoxicity. However, while modification of Tup stereochemistry has only minor effect on the tubulysins cytotoxicity, Tuv stereochemistry is critically important and modification of either Tuv stereocentre produced a dramatic drop in cytotoxicity. © 2013 Elsevier Ltd. All rights reserved.

Shankar S.P.,Polytechnic of Milan | Jagodzinska M.,Polytechnic of Milan | Jagodzinska M.,Jagiellonian University | Malpezzi L.,Polytechnic of Milan | And 8 more authors.
Organic and Biomolecular Chemistry | Year: 2013

Tubulysins are cytotoxic natural products with promising anti-cancer properties, originally isolated from myxobacterial cultures. Structurally, tubulysins are tetrapeptides, incorporating three unusual (Mep, Tuv and Tup) and one proteinogenic amino acid (Ile). Here we describe the synthesis and structure-activity relationship studies of novel tubulysin U and V analogues, with variations in the central Tuv fragment, which is known to be of paramount importance for tubulysins' potency and hence cytotoxicity, but has seldom been modified in previous studies. Specifically, we replaced the natural iso-propyl and acetoxy functionalities with other structurally related groups. In general, the new analogues showed much lower potency relative to native tubulysin U. However, one of the synthetic analogues (1f) having a MOM function replacing the acetyl group exhibited a 22 nM IC50 on the HT-29 cell line which is comparable to the IC50 displayed by tubulysin U (3.8 nM). Furthermore, the synthetic methodology reported herein was found to be flexible enough to deliver different core-modified tubulysin analogues and hence may be regarded as a scalable and convenient strategy for the chemical generation of novel tubulysin analogues. © 2013 The Royal Society of Chemistry.

Pinna G.,University of Sassari | Loriga G.,Istituto di Farmacologia Traslazionale | Pinna G.A.,University of Sassari | Chelucci G.,University of Sassari
Molecules | Year: 2013

In this paper we report the synthesis of new compounds based on the pyrazole and isoxazole framework fused to a cycloalkene unit, and bearing as a substituent the 1-piperidinyl group as new examples of potential antipsychotic molecules. The general synthesis involves the acylation of a chloro-substituted cyclic ketone with a 1-substituted piperidine-4-carboxylate derivative, followed by heterocyclization of the formed 1,3-dioxo compound with a hydrazine or hydroxylamine. © 2013 by the authors.

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