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Synthesis and Evaluation of Novel Cyclopropane …

T1 - Cyclopropane-derived peptidomimetics. Design, synthesis, evaluation, and structure of novel HIV-1 protease inhibitors

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Organic 1 — Master Organic Chemistry

During the past decade, donor–acceptor (D–A) cyclopropanes have enjoyed a renaissance as easily available building blocks. Although the basic chemistry in this field was developed by Wenkert and Reissig in the 1970s and 1980s, many groups have recently utilized the unique features of this special class of three-membered rings. These highly polarized strained systems easily undergo cycloadditions, rearrangements, and ring-opening reactions. Thus, they are an ideal starting point for the synthesis of carbo- and heterocycles and have been used in the preparation of natural products.

Cyclopropane rings can be introduced into alkenes by addition of carbene.

Electroreduction of α-alkylated styrenes (1) in the presence of diphenyl succinate (2) or glutarate (3) in ,-dimethylformamide (DMF) using an undivided cell equipped with Zn plates as the anode and the cathode brought about regio- and stereoselective efficient double carbon-carbon bond formation between the two olefinic carbon atoms of 1 and one carbonyl carbon atom of 2 or 3, followed by lactonization to give the corresponding five- (4) or six-membered spiro-lactones (5) possessing cyclopropane rings in moderate to good yields.

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These reactions provide rapid synthetic routes to the preparations of spirobarbiturates and spirothiobarbiturates bearing cyclopropane rings.

As part of an ongoing effort to discover potential COA-Cl analogs with higher angiogenic activity, we studied the structure–activity relationship of the two hydroxymethyl groups bound to the cyclobutane ring at the 2′ and 3′ position, or around the functional group at the 2-position of the purine skeleton of COA-Cl. In this study, we designed five structurally relevant novel COA-Cl analogs by replacing the 2′,3′-bis-hydroxymethylated cyclobutane ring of COA-Cl with a hydroxymethylated cyclopropane ring. Specifically, three novel COA-Cl derivative racemates (2a and b) and an achiral compound (2c) with a mono-hydroxymethylated cyclopropane ring at the 9-position in the 2-chloroadenine moiety, and two novel COA-Cl analog racemates (2d) and a chiral compound (2e) with a bis-hydroxymethylated cyclopropane ring at the 9-position in the 2-chloroadenine skeleton, were synthesized and evaluated using human umbilical vein endothelial cells (HUVECs) as shown in .

In conclusion, we designed five structurally relevant COA-Cl analogs, which were nucleosides with mono or bis-hydroxymethylated cyclopropane rings at the 9-position in the 2-chloroadenine moiety (2ae), Furthermore, compound 2b exhibited a greater angiogenic activity than the other compounds did at 100 µM, which was also superior to the potency of COA-Cl (1a). Overall, our data may serve as the basis for further modification experiments to identify additional potent candidates that induce tube formation.

Click Chemistry Publications - Scripps Research Institute

Modular Synthesis of a New Family of Tripodal Ligands, all-cis-1,2,3-Tris(diphenylphosphinomethyl)cyclopropane and Relatives.

Structurally, colchicine (1) possesses an unusual 6–7–7 tricyclic ring system, and NCME (2) possesses a 6–7–6 carbocyclic skeleton. The stereocenter at C-7 and the a-configured chiral axis defined by the pivot bond joining the A and C rings, and the regioselective construction of the highly oxidized tropolone C-ring, represent formidable synthetic challenges. It is noteworthy that another colchicinoid β-lumicolchicine (3) has a novel tetracyclic 6–7–4–5 membered ring system with three stereocenters, and α-lumicolchicine (4) has a unique nonacyclic 6–7–4–5–4–5–4–7–6 ring skeleton with ten stereocenters.

AB - Toward establishing the general efficacy of using trisubstituted cyclopropanes as peptide mimics to stabilize extended peptide structures, the cyclopropanes 20a-d were incorporated as replacements into 9-13, which are analogues of the known HIV-1 protease inhibitors 14 and 15. The syntheses of 20a-d commenced with the Rh2[5(S)-MEPY]4-catalyzed cyclization of the allylic diazoesters 16a-d to give the cyclopropyl lactones 17a-d in high enantiomeric excess. Opening of the lactone moiety using the Weinreb protocol and straightforward refunctionalization of the intermediate amides 18a-d gave 20a-d. A similar sequence of reactions was used to prepare the N-methyl-2- pyridyl analogue 28. Coupling of 20a-d and 28 with the known diamino diol 22 delivered 9-13. Pseudopeptides 9-12 were found to be competitive inhibitors of wild-type HIV-1 protease in biological assays having K(i)s of 0.31-0.35 nM for 9, 0.16-0.21 nM for 10, 0.47 nM for 11, and 0.17 nM for 12; these inhibitors were thus approximately equipotent to the known inhibitor 14 (IC50 = 0.22 nM) from which they were derived. On the other hand 13 (K(i) = 80 nM) was a weaker inhibitor than its analogue 15 (K(i) = 0.11 nM). The solution structures of 9 and 10 were analyzed by NMR spectroscopy and simulated annealing procedures that included restraints derived from homo- and heteronuclear coupling constants and NOEs; because of the molecular symmetry of 9 and 10, a special protocol to treat the NOE data was used. The final structure was checked by restrained and free molecular dynamic calculations using an explicit DMSO solvent box. The preferred solution conformations of 9 and 10 are extended structures that closely resemble the three-dimensional structure of 10 bound to HIV-1 protease as determined by X- ray crystallographic analysis of the complex. This work convincingly demonstrates that extended structures of peptides may be stabilized by the presence of substituted cyclopropanes that serve as peptide replacements. Moreover, the linear structure enforced in solution by the two cyclopropane rings in the pseudopeptides 9-12 appears to correspond closely to the biologically active conformation of the more flexible inhibitors 14 and 15. The present work, which is a combination of medicinal, structural, and quantum chemistry, thus clearly establishes that cyclopropanes may be used as structural constraints to reduce the flexibility of linear pseudopeptides and to help enforce the biologically active conformation of such ligands in solution.

that perform the introduction of cis-cyclopropane rings at proximal and distal ..
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  • General & Introductory Chemistry

    A broad range of methods for the construction of cyclopropane rings have been reported and are frequently used

  • Organic Chemistry - Real-life applications - Science Clarified

    Cyclopropane-derived peptidomimetics. Design, synthesis, evaluation, and structure of novel HIV-1 protease inhibitors

  • everyday life, but this could not be further from the truth

    Thus,cmaA2 is required for the synthesis of thetrans cyclopropane rings of both the methoxymycolates and ketomycolates.

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Important dates in the history of lipids ..

Our reaction conditions were successfully extended to the synthesis of 1,3-chloroselenated products. Phthalimide- and phenyl-substituted three-membered rings were converted smoothly with commercially available phenylselenyl chloride (). The corresponding selenium-containing products were obtained in 66 and 83% yield. Formation of 8a was much faster than 8b. Because of the relative instability of corresponding aliphatic selenyl chlorides, we did not attempt transformations with these reagents. Analogous experiments with phenylselenyl bromide and thio- and selenocyanates showed no conversion, and the starting material was recovered.

Organic Chemistry - Real-life applications - Science …

The chirality of cyclopropane 28 was completely transferred to cyclohexenone 29,[] thus confirming that cyclohexenones can be enantioselectively synthesized from optically pure cyclopropanes. The highly functionalized decalin rings 33 and 35 were also prepared in high yields from bicyclic substrates with high regioselectivity. Five-membered ring isomerization products were isolated in 19% and 11% yields from substrates 32 and 34, respectively under the standard reaction conditions.[] Interestingly, no five-membered ring isomerization product was observed in the monocyclic system even in the absence of a CO atmosphere.

Cyclopropane | Wiki | Everipedia

N2 - Toward establishing the general efficacy of using trisubstituted cyclopropanes as peptide mimics to stabilize extended peptide structures, the cyclopropanes 20a-d were incorporated as replacements into 9-13, which are analogues of the known HIV-1 protease inhibitors 14 and 15. The syntheses of 20a-d commenced with the Rh2[5(S)-MEPY]4-catalyzed cyclization of the allylic diazoesters 16a-d to give the cyclopropyl lactones 17a-d in high enantiomeric excess. Opening of the lactone moiety using the Weinreb protocol and straightforward refunctionalization of the intermediate amides 18a-d gave 20a-d. A similar sequence of reactions was used to prepare the N-methyl-2- pyridyl analogue 28. Coupling of 20a-d and 28 with the known diamino diol 22 delivered 9-13. Pseudopeptides 9-12 were found to be competitive inhibitors of wild-type HIV-1 protease in biological assays having K(i)s of 0.31-0.35 nM for 9, 0.16-0.21 nM for 10, 0.47 nM for 11, and 0.17 nM for 12; these inhibitors were thus approximately equipotent to the known inhibitor 14 (IC50 = 0.22 nM) from which they were derived. On the other hand 13 (K(i) = 80 nM) was a weaker inhibitor than its analogue 15 (K(i) = 0.11 nM). The solution structures of 9 and 10 were analyzed by NMR spectroscopy and simulated annealing procedures that included restraints derived from homo- and heteronuclear coupling constants and NOEs; because of the molecular symmetry of 9 and 10, a special protocol to treat the NOE data was used. The final structure was checked by restrained and free molecular dynamic calculations using an explicit DMSO solvent box. The preferred solution conformations of 9 and 10 are extended structures that closely resemble the three-dimensional structure of 10 bound to HIV-1 protease as determined by X- ray crystallographic analysis of the complex. This work convincingly demonstrates that extended structures of peptides may be stabilized by the presence of substituted cyclopropanes that serve as peptide replacements. Moreover, the linear structure enforced in solution by the two cyclopropane rings in the pseudopeptides 9-12 appears to correspond closely to the biologically active conformation of the more flexible inhibitors 14 and 15. The present work, which is a combination of medicinal, structural, and quantum chemistry, thus clearly establishes that cyclopropanes may be used as structural constraints to reduce the flexibility of linear pseudopeptides and to help enforce the biologically active conformation of such ligands in solution.

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