1,721,147 research outputs found
Total Synthesis of δ-Sanshool and Analogues Thereof
No full textTwo simple synthetic approaches were developed for the total synthesis of δ-sanshool, an isobutylamide characterized by a C14 pentaunsaturated chain with all trans double bonds and proposed as a promising lead for the treatment of type-1 diabetes due to its dual activity on cannabinoid (CB) receptors. The syntheses are based on a suitably protected core fragment derived from 1,4-butanediol. These strategies also enable the preparation of small libraries of chemical analogues modified at either the polyunsaturated alkyl chain or the amidic head for use in SAR studies
New solid-supported reagents (SSRs) for selective acylation of amines
No full textThe pyrimidine linker (4) was prepared by solid phase synthesis starting from Merrifield resin. Acylation of 4 with different acyl chlorides gave polymerbound 4-acyloxypyrimidines (2a-c), which proved to be useful solid-supported reagents for the selective acylation of amines. Their use in solution combinatorial chemistry has been also envisaged. (author abst.
Preparation of a set of 4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-ones as potential Hsp90 ligands
No full textA synthetic route for the preparation of 4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-ones characterized by a decorated benzyl moiety at different positions of the five-membered ring has been developed, and some compounds have been tested as Hsp90 ligands. One of them displayed IC50 = 50 μM representing an interesting starting point for further investigations. © 2008 Elsevier Ltd. All rights reserved
Fibroblast growth factors and their inhibitors
No full textFibroblast growth factors (FGFs) are members of a family of polypeptides synthesized by a variety of cell types during the processes of embryonic development and in adult tissues. FGFs have been detected in normal and malignant cells and show a biological profile that includes mitogenic and angiogenic activity with a consequent crucial role in cell differentiation and development. To activate signal transduction pathways, FGFs use a dual receptor system based on tyrosine kinases and heparan sulfate (HS) proteoglycans. Based on these considerations, a variety of inhibitors able to block the interactions between FGFs and their receptors have been designed and investigated for their biological properties related to antiangiogenesis and antitumor activity. In this paper, in addition to an extensive description of the FGF family members, we report several compounds acting as FGF inhibitors by direct interaction with the growth factors. Suramin and other diverse polyanionic polysulfated and polysulfonated compounds are described, with a particular focus on suradistas. For this class of molecules, by means of molecular modeling procedures, a binding model to FGF-2 has been proposed and the structure-activity relationships of suradistas have been analyzed on the basis of the computational model described
Efficient synthesis of iminoctadine, a potent antifungal agent and polyamine oxidase inhibitor (PAO)
No full textIminoctadine (1,17-diguanidino-9-azaheptadecane), isolated from a mixture of polyamines and guanidines known as guazatine that is used in agriculture as a fungicide, showed interesting activity as human antifungal agent and PAO inhibitor. In this paper, we propose a straightforward synthetic strategy for obtaining pure iminoctadine tris(trifluoroacetate) in high overall yield. © Georg Thieme Verlag Stuttgart
The bioisosteric concept applied to cannabinoid ligands
No full textBioisosterism is widely used in medicinal chemistry as an approach aimed at either rationally modifying a hit compound into a more potent and/or selective molecule or a lead compound into a more drug-like one. Two different cannabinoid receptors have been cloned from mammalian tissues, the CB1 receptor, mostly expressed in brain, and the CB2 receptor, mostly expressed in the immune system, both regulating a variety of physiological functions. Synthetic cannabinoids have been developed that act as highly selective agonists or antagonists/inverse agonists at one or other of these receptor types with the ultimate goal of modulating the endocannabinoid system. This review takes into account the use of the bioisosteric substitution in the field of cannabinoid ligands as a tool for improving both their pharmacodynamic and pharmacokinetic propertie
Ligandi TRPV1
No full textLa presente invenzione concerne composti aventi alta affinità, capaci di legare il recettore canale permeabile ai cationi transient receptor potential, sottofamiglia Vanilloide, tipo 1 o TRPV1. Essendo questo recettore coinvolto in processi dolorosi e in risposte infiammatorie neurogene ed essendo sovra-regolato durante condizioni di dolore cronico, i composti dell’invenzione trovano particolare applicazione in tutte le condizioni mediche coinvolgenti detti recettori, in particolare come agenti per la terapia del dolore e/o antiinfiammatoria e/o della terapia della cefalea a grappolo e/o antiossidante e/o per la terapia antitumorale. Inoltre, la struttura chimica di questi composti fornisce l’opportunità di sviluppare nuovi radiofarmaci per la Positron Emission Tomography (PET) imaging. Questi radiofarmaci sono di notevole importanza per la mappatura dei recettori TRPV1 in condizioni (pato)fisiologiche
The 4-Quinolone-3-carboxylic Acid Motif as a Multivalent Scaffold in Medicinal Chemistry
No full textQuinolones are among the most common frameworks present in the bioactive molecules and hence represent an attractive starting point for the design of combinatorial libraries. Since 1962 4-quinolone-3-carboxylic acid derivatives are clinically used as antibacterial agents worldwide. Currently, fluoroquinolones are approved by the WHO as second-line drugs to treat tuberculosis (TB), and their use in multidrug-resistant (MDR)-TB is increasing due to the fact that they have a broad and potent spectrum of activity and can be administered orally. In the last years, quinolones endowed with "nonclassical" biological activities, such as antitumor, anti-HIV-1 integrase, cannabinoid receptor 2 agonist/antagonist activities, have been reported by our research group as well as by other researchers. This review focuses on the 4-quinolone-3-carboxylic acid motif as a privileged structure in medicinal chemistry for obtaining new compounds possessing antibacterial, antitumor, anti-HIV, and cannabinoid receptors modulating activities. Synthetic approaches, structure-activity relationships, mechanisms of action, and therapeutic potentials of these novel classes of pharmacologically active compounds are presented
Chemistry of GABAB receptor ligands: focus on agonists and antagonists
No full textSince the discovery of GABAB receptor by Norman G. Bowery and coworkers in 1980, a striking endeavour was made by industrial and academic researchers to develop GABAB receptor ligands for therapeutic application in a variety of diseases associated with dysfunctions of the gabaergic system. Although baclofen (Lioresal) is still the only approved GABAB receptor agonist, this sustained research effort has produced many new compounds which are able to exert GABAB agonist, partial agonist or antagonist activity. This chapter presents an overview of the outcomes in this field, with a special focus on the chemistry, structure–activity relationship and mechanism of action of several GABA and baclofen analogues, derivatives and bioisosteres. © Springer International Publishing Switzerland 2016
The allosteric modulation of the GABAB receptor: a medicinal chemistry perspective
No full textSince its cloning, the GABAB receptor has progressively become a target for potential drugs to be used in the treatment of a wide range of pathological conditions such as spasticity, pain, drug addiction, epilepsy, anxiety, mood disorders. Baclofen, the only GABAB receptor agonist currently approved for the treatment of muscle rigidity and spasm associated with multiple sclerosis or spinal cord injury, suffers from a number of side effects which hamper its clinical use. As a result, there has been a strong impetus for the development of positive allosteric modulators that modulate the physiological mechanisms of GABAergic regulation and are expected to have a much lower side effect potential than orthosteric ligands. Herein, the major structural classes of GABAB allosteric modulators are described with an emphasis on structure–activity relationships (SAR) and synthesis of the main representatives of each class. Medicinal chemistry strategies to overcome issues related to allosteric modulators development are also discussed. © Springer International Publishing Switzerland 2016
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