Bicyclic Urea Research Articles

Advanced Pyrrolidine-Carbamate Self-Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release.

Amine‐carbamate self‐immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine‐carbamate SI spacer with a tertiary amine handle which strongly accelerates the spacer cyclization to give a bicyclic urea and the free hydroxy groups of either cytotoxic (Camptothecin) or immunostimulatory (Resiquimod) drugs. In silico conformational analysis and pK a calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state‐of‐art analogues.

Cholesteryl ester transfer protein (CETP) inhibitors based on cyclic urea, bicyclic urea and bicyclic sulfamide cores

Cholesteryl ester transfer protein (CETP) inhibitors reduce the transfer of cholesteryl esters from the high-density lipoprotein (HDL-C) to apolipoprotein such as VLDL/LDL, with exchange of triglycerides. Thus, this inhibition increases the HDL-C levels, which is believed to lower the risk for heart disease and stroke. We report here a series of CETP inhibitors based on the cyclic, bicyclic urea and sulfamide cores. These CETP inhibitors exemplified by 15, 31, and 45 demonstrated in vitro potency in inhibiting the CETP transfer activity, and 15, 31 showing in vivo efficacy to increase HDL-C levels in cynomolgus-CETP transgenic mice. The synthesis and biological evaluations of these CETP inhibitors are described.

Synthesis of a protected 2-aminocyclobutanone as a modular transition state synthon for medicinal chemistry

The hydrochloride salt of ɑ-aminocyclobutanone protected as its dimethyl acetal 2,2-dimethoxycyclobutan-1-aminium chloride (3) has been prepared as a modular synthon for convenient access to cyclobutanone-containing lead inhibitors of hydrolase enzymes including serine proteases and metalloproteases. Protected ɑ-aminocyclobutanone 3 was converted to representative amide and sulfonamide-functionalized 2-aminocyclobutanone derivatives. Reaction of the amino acetal 3 with phenyl isothiocyanate afforded the bicyclic urea 1-hydroxyl-2,4-diazabicyclo[3.2.0]heptane-3-thione (9) as confirmed by a single crystal X-ray structure.

An easy access to fused chromanones via rhodium catalyzed oxidative coupling of salicylaldehydes with heterobicyclic olefins

Herein we describe a detailed study on the rhodium catalyzed oxidative coupling of salicylaldehydes with heterobicyclic olefins such as diazabicyclic olefins and urea-derived bicyclic olefins. The developed method provides an ideal route to fused chromanone systems in a single synthetic step. Moreover, the scope of this methodology was extended to different oxa/aza-bridged bicyclic urea derivatives.

Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin®

β-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C β-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C β-lactamases in vitro. It effectively restored imipenem’s activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.

ChemInform Abstract: Desymmetrization of meso‐2,5‐Diallylpyrrolidinyl Ureas Through Asymmetric Palladium‐Catalyzed Carboamination: Stereocontrolled Synthesis of Bicyclic Ureas.

AbstractThis novel title reaction allows the asymmetric synthesis of bicyclic urea derivatives bearing three stereocenters.

Desymmetrization of meso-2,5-diallylpyrrolidinyl ureas through asymmetric palladium-catalyzed carboamination: stereocontrolled synthesis of bicyclic ureas.

Desymmetrization of meso-2,5-diallylpyrrolidinyl ureas through asymmetric palladium-catalyzed carboamination: stereocontrolled synthesis of bicyclic ureas.

Asymmetric Total Synthesis of (+)‐Merobatzelladine B

Asymmetric Total Synthesis of (+)‐Merobatzelladine B

Electronic Structure, Binding Energy, and Solvation Structure of the Streptavidin−Biotin Supramolecular Complex: ONIOM and 3D-RISM Study

We studied the electronic structure of the binding site of the streptavidin-biotin complex by using the ONIOM method at the HF/STO-3G:UFF level and obtained the solvation structure of the complex by using the statistical-mechanical, three-dimensional molecular theory of solvation (aka three-dimensional reference interaction site model, 3D-RISM-KH). All the streptavidin residues located within 3 A of the biotin residue were included in the quantum mechanical (QM) layer. In total, 16 residues including biotin with 274 atoms were in the QM layer, in which five residues are responsible for the hydrophobic interactions and nine residues for the hydrogen-bonding/electrostatic interaction with biotin. We found a geometry change of the urea moiety of the biotin bound in the network of van der Waals and polar interactions. Compared to the isolated biotin, the bridging C-C bond of the biotin urea moiety in the binding site increases in length as a result of the pi-sigma interaction with the surrounding streptavidin Trp residues. This extends the previous picture of the geometry change from the ureido group to the whole bicyclic urea moiety. We have evaluated the performance of 15 density functional methods and 11 basis sets by single point calculation for the binding energy of the optimized cooperative binding complex structure. Closest to the experimental value of 18.3 kcal/mol is the binding free energy of 19.6 kcal/mol obtained for the AN model at B3LYP/6-31G(d):UFF//HF/STO-3G:UFF level. The hybrid DFT methods with enhanced assessment for nonbonded interactions such as PBE1PBE, MPW1B95, and MPWB1K can also give accurate binding energy with the use of diffuse functionals (i.e., mPWB1K/6-31+G(d)). The 3D hydration structure of the unliganded streptavidin and the streptavidin-biotin complex obtained by using the 3D-RISM-KH molecular theory of solvation shows there is one immobilized water molecule at the biotin urea moiety, acting as a water bridge between the sulfur and the nitrogen of the NH group close to Ser45. This suggests that, in the docking process, biotin replaces six of the seven water molecules attached to the unliganded streptavidin binding site, and one remaining water molecule is squeezed into the gap between the Btn, Tyr43, Ser45, Trp92, and Trp79 residues in the binding pocket.

The origins of femtomolar protein-ligand binding: hydrogen-bond cooperativity and desolvation energetics in the biotin-(strept)avidin binding site.

The unusually strong reversible binding of biotin by avidin and streptavidin has been investigated by density functional and MP2 ab initio quantum mechanical methods. The solvation of biotin by water has also been studied through QM/MM/MC calculations. The ureido moiety of biotin in the bound state hydrogen bonds to five residues, three to the carbonyl oxygen and one for each--NH group. These five hydrogen bonds act cooperatively, leading to stabilization that is larger than the sum of individual hydrogen-bonding energies. The charged aspartate is the key residue that provides the driving force for cooperativity in the hydrogen-bonding network for both avidin and streptavidin by greatly polarizing the urea of biotin. If the residue is removed, the network is disrupted, and the attenuation of the energetic contributions from the neighboring residues results in significant reduction of cooperative interactions. Aspartate is directly hydrogen-bonded with biotin in streptavidin and is one residue removed in avidin. The hydrogen-bonding groups in streptavidin are computed to give larger cooperative hydrogen-bonding effects than avidin. However, the net gain in electrostatic binding energy is predicted to favor the avidin-bicyclic urea complex due to the relatively large penalty for desolvation of the streptavidin binding site (specifically expulsion of bound water molecules). QM/MM/MC calculations involving biotin and the ureido moiety in aqueous solution, featuring PDDG/PM3, show that water interactions with the bicyclic urea are much weaker than (strept)avidin interactions due to relatively low polarization of the urea group in water.

Synthesis of Cyclic Nitramines From Products of the Cyclocondensation Reaction of Guanidine With 2,3,5,6-Tetrahydroxypiperazine-1,4-dicarbaldehyde

The reaction of 2,3,5,6-tetrahydroxypiperazine-1,4-dicarbaldehyde (1) with guanidine hydrochloride in hydrochloric acid can be controlled to give 2,6-diiminododecahydrodiimidazo[4,5-b:4′,5′-e] pyrazine (2a) or the cis isomer of 4,5-diamino-2-iminoimidazolidine (4). Compound (4) reacts with formaldehyde, or formic acid followed by reduction, to give 2-iminooctahydroimidazo[4,5-d] imidazole (7). Treatment of (2a) or (7) with nitric acid gives dinitro derivatives that were isolated as nitric acid salts of the cyclic guanidines. Reaction of the dinitro derivatives with nitric acid/acetic anhydride in the presence of chloride ion gives 4,8-dinitro-2,6-bis( nitroimino ) dodecahydrodiimidazo -[4,5-b:4′,5′-e] pyrazine (3a) and 1,3-dinitro-5-( nitroimino ) octahydroimidazo [4,5-d] imidazole (9). The reaction of (7) with nitric acid/ trifluoroacetic anhydride was controlled to give either the tetranitro or a dinitro bis ( trifluoroacetyl ) derivative of the corresponding bicyclic urea.

Anti-Bredt molecules

An “anti-Bredt” bicyclic urea, 1,3-diazabicyclo-[3.3.1] nonan-2-one, was synthesized. At 125° this urea polymerized thermally and at 98° it rapidly polymerized under the influence of phosphoric acid. Two isomeric ureas, lacking the anti-Bredt feature, did not polymerize under similar conditions.

The Synthesis and Polymerization of 1,3-Disubstituted Cyclohexanes

Abstract The synthesis of cis- and trans-1,3-diisocyanatocyclohexane is described. With water the cis-diisocyanate gave a bicyclic urea and a polyurea, which decomposed on heating to the bicyclic urea, and the trans-diisocyanate formed a polyurea. cis-1,3-Diisocyanatocyclohexane was polymerized using sodium cyanide as initiator to give soluble polymers which contained little or no residual isocyanato groups and hence cyclopolymerization had occurred. The polymers were thermally unstable and depolymerized quantitatively to monomer in the temperature range 270-370°. Two different structural units are possible for the cyclopolymer and the proportions of each unit were estimated by a quantitative aminolysis using di-n-butylamine. trans-1,3-Di-isocyanatocyclohexane did not polymerize under similar conditions.