33900-28-6Relevant academic research and scientific papers
Pharmacodynamic and pharmacokinetic profiles of a neurotensin receptor type 2 (NTS2) analgesic macrocyclic analog
Chartier, Magali,Desgagné, Michael,Sousbie, Marc,Rumsby, Charles,Chevillard, Lucie,Théroux, Léa,Haroune, Lounès,C?té, Jér?me,Longpré, Jean-Michel,Boudreault, Pierre-Luc,Marsault, éric,Sarret, Philippe
, (2021/07/07)
The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8–13) analog. The Tyr11 residue of NT(8–13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys8 and Trp11 to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (Ki 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t1/2 > 24 h) compared with NT (t1/2 ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED50 = 4.6 μg/kg) and tonic (ED50 = 7.1 μg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.
Asymmetric and Geometry-Selective α-Alkenylation of α-Amino Acids
Abas, Hossay,Mas-Roselló, Josep,Amer, Mostafa Mahmoud,Durand, Derek J.,Groleau, Robin R.,Fey, Natalie,Clayden, Jonathan
supporting information, p. 2418 - 2422 (2019/02/09)
Both E- and Z-N′-alkenyl urea derivatives of imidazolidinones may be formed selectively from enantiopure α-amino acids. Generation of their enolate derivatives in the presence of K+ and [18]crown-6 induces intramolecular migration of the alkeny
Synthesis of 2-D-L-tryptophan by sequential Ir-catalyzed reactions
Vallakati, Ravikrishna,Plotnikov, Abel T.,Altman, Ryan A.
, p. 2261 - 2264 (2019/03/04)
Herein, we report a practical synthesis of 2-D-l-tryptophan via sequential Ir-catalyzed C–H borylation, and Ir-catalyzed C-2-deborylative deuteration steps. In this synthetic sequence, deprotection of the Boc and methyl ester groups proved challenging, due to replacement of deuterium with hydrogen. However, mild deprotection conditions were developed to avoid this D/H scrambling. Further, 2-D-L-Tryptophan is stable in many buffers used for biological studies.
Selective Reductive Elimination at Alkyl Palladium(IV) by Dissociative Ligand Ionization: Catalytic C(sp3)?H Amination to Azetidines
Nappi, Manuel,He, Chuan,Whitehurst, William G.,Chappell, Ben G. N.,Gaunt, Matthew J.
supporting information, p. 3178 - 3182 (2018/02/28)
A palladium(II)-catalyzed γ-C?H amination of cyclic alkyl amines to deliver highly substituted azetidines is reported. The use of a benziodoxole tosylate oxidant in combination with AgOAc was found to be crucial for controlling a selective reductive elimination pathway to the azetidines. The process is tolerant of a range of functional groups, including structural features derived from chiral α-amino alcohols, and leads to the diastereoselective formation of enantiopure azetidines.
Unlocking the potential of phenacyl protecting groups: CO2-based formation and photocatalytic release of caged amines
Speckmeier, Elisabeth,Klimkait, Michael,Zeitler, Kirsten
, p. 3738 - 3745 (2018/04/14)
Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical biology and material research applications. A robust, highly efficient, and sustainable method for the formation of phenacyl-based carbamate esters was developed using CO2 for the in situ preparation of the intermediate carbamates. Our mild and broadly applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection protocol using visible light. A key feature of the [Ru(bpy)3](PF6)2-catalyzed method is the use of ascorbic acid as reductive quencher in a neutral, buffered, two-phase acetonitrile/water mixture, granting fast and highly selective deprotection for all presented examples.
Synthesis, biological evaluation, and molecular modeling studies of chiral chloroquine analogues as antimalarial agents
Kondaparla, Srinivasarao,Debnath, Utsab,Dola, Vasantha Rao,Sinha, Manish,Katti, Seturam B.,Soni, Awakash,Srivastava, Kumkum,Puri, Sunil K.
, (2019/01/05)
In a focused exploration, we designed, synthesized, and biologically evaluated chiral conjugated new chloroquine (CQ) analogues with substituted piperazines as antimalarial agents. In vitro as well as in vivo studies revealed that compound 7c showed potent activity (in vitro 50% inhibitory concentration, 56.98 nM for strain 3D7 and 97.76 nM for strain K1; selectivity index in vivo [up to at a dose of 12.5 mg/kg of body weight], 3,510) as a new lead antimalarial agent. Other compounds (compounds 6b, 6d, 7d, 7h, 8c, 8d, 9a, and 9c) also showed moderate activity against a CQ-sensitive strain (3D7) and superior activity against a CQ-resistant strain (K1) of Plasmodium falciparum. Furthermore, we carried out docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of all in-house data sets (168 molecules) of chiral CQ analogues to explain the structure-activity relationships (SAR). Our new findings specify the significance of the H-bond interaction with the side chain of heme for biological activity. In addition, the 3D-QSAR study against the 3D7 strain indicated the favorable and unfavorable sites of CQ analogues for incorporating steric, hydrophobic, and electropositive groups to improve the antimalarial activity.
Cyclotryptophan Mycotoxins: Short Synthesis of the Desymmetrized meso -Chimonantine Core of Leptosin C
Olaizola, Iurre,Abdine, Racha Abed Ali,Dhimane, Hamid,Dalko, Peter I.
, p. 391 - 396 (2016/12/24)
The desymmetrized meso-chimonantine core of leptosin C was prepared in a short stereoselective convergent sequence in 5 steps as the longest linear path from methyl l-tryptophan hydrochloride as starting material. The key step of this approach was a diastereoselective [4+2] cycloaddition between the bromooxindole and tryptophan derivatives allowing to define the adjacent quaternary benzylic centers in a high chemical yield.
AgNTf2-mediated arylation of bromopyrroloindolines
Sato, Soichiro,Hirayama, Azusa,Adachi, Tohma,Kawauchi, Daichi,Ueda, Hirofumi,Tokuyama, Hidetoshi
, p. 1940 - 1957 (2017/10/24)
The silver(I)-mediated arylation of bromopyrroloindolines was developed. The selection of silver salts was crucial to obtain arylated compounds in high yields. Among the various tested silver(I) salts, AgNTf2 was the most effective agent for ar
An environmentally friendly protocol for oxidative halocyclization of tryptamine and tryptophol derivatives
Xu, Jun,Tong, Rongbiao
supporting information, p. 2952 - 2956 (2017/07/24)
An environmentally friendly and efficient protocol (KX/oxone) for oxidative halocyclization of tryptamine/tryptophol derivatives was developed and demonstrated with 28 examples and concise total synthesis of cyclotryptamine alkaloid protubonines A and B. The distinct advantage of this protocol over all previous methods is that no organic byproduct is generated from a halogenating agent or oxidant, thus greatly reducing the environmental impact of halocyclization and facilitating the post-reaction purification.
Design, synthesis, and evaluation of novel Akt1 inhibitors based on an indole scaffold
Yang, Dezhi,Tong, Dongdong,Zhang, Qian,Wang, Yongtao,Sun, Jing,Zhang, Fenghe,Zhao, Guisen
, p. 791 - 803 (2017/09/30)
A new series of potential Akt1 inhibitors with indole scaffold were designed and synthesized. The antiproliferative activity against PC-3 cell line and enzyme inhibitory activity against Akt1 were evaluated. Among them, some compounds showed much more potent antiproliferative activity and stronger Akt1 inhibitory activity compared to the positive control of GSK690693. In particular, compound 19b exhibited the most potent inhibitory activity against Akt1 with inhibition rate of 70.3% at a concentration of 10?nm. Furthermore, compound 19b could dose dependently reduce the phosphorylation of the downstream GSK3β protein in the PC-3 cell line and displayed fivefold higher antiproliferative activity against PC-3 cell line with IC50 value of 3.1?±?0.1?μm than positive control (15.5?±?0.4?μm). Herein, compound 19b may serve as a promising lead for further optimization and development of novel Akt1 inhibitors based on an indole scaffold.
