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1.
J Org Chem ; 89(10): 6651-6663, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38663026

ABSTRACT

This article outlines the process development leading to the manufacture of 800 g of BMS-986189, a macrocyclic peptide active pharmaceutical ingredient. Multiple N-methylated unnatural amino acids posed challenges to manufacturing due to the lability of the peptide to cleavage during global side chain deprotection and precipitation steps. These issues were exacerbated upon scale-up, resulting in severe yield loss and necessitating careful impurity identification, understanding the root cause of impurity formation, and process optimization to deliver a scalable synthesis. A systematic study of macrocyclization with its dependence on concentration and pH is presented. In addition, a side chain protected peptide synthesis is discussed where the macrocyclic protected peptide is extremely labile to hydrolysis. A computational study explains the root cause of the increased lability of macrocyclic peptide over linear peptide to hydrolysis. A process solution involving the use of labile protecting groups is discussed. Overall, the article highlights the advancements achieved to enable scalable synthesis of an unusually labile macrocyclic peptide by solid-phase peptide synthesis. The sustainability metric indicates the final preparative chromatography drives a significant fraction of a high process mass intensity (PMI).


Subject(s)
Macrocyclic Compounds , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/chemical synthesis , Peptides, Cyclic/chemistry , Peptides, Cyclic/chemical synthesis , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/chemistry , Peptides/chemistry , Peptides/chemical synthesis , Solid-Phase Synthesis Techniques , Molecular Structure
2.
J Org Chem ; 84(13): 8360-8379, 2019 07 05.
Article in English | MEDLINE | ID: mdl-30905152

ABSTRACT

An intramolecular arene alkylation reaction has been developed using the organic photocatalyst 4CzIPN, visible light, and N-(acyloxy)phthalimides as radical precursors. Reaction conditions were optimized via high-throughput experimentation, and electron-rich and electron-deficient arenes and heteroarenes are viable reaction substrates. This reaction enables access to a diverse set of fused, partially saturated cores which are of high interest in synthetic and medicinal chemistry.

3.
J Org Chem ; 83(16): 9119-9124, 2018 08 17.
Article in English | MEDLINE | ID: mdl-29966423

ABSTRACT

Aziridine aldehyde-driven macrocyclization of peptides is a powerful tool for the construction of biologically active macrocycles. While this process has been used to generate diverse collections of cyclic molecules, its mechanistic underpinnings have remained unclear. To enable progress in this area we have carried out a mechanistic study, which suggests that the cyclization owes its efficiency to a combination of electrostatic attraction between the termini of a nitrilium ion intermediate and intramolecular hydrogen bonding. Our model adequately explains the experimentally observed trends, including diastereoselectivity, and should facilitate the development of other macrocyclization reactions.


Subject(s)
Aldehydes/chemistry , Aziridines/chemistry , Models, Chemical , Peptides/chemistry , Cyclization , Models, Molecular , Molecular Conformation , Thermodynamics
4.
Drug Discov Today Technol ; 26: 3-10, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29249240

ABSTRACT

Constrained peptides pose tremendous value in drug discovery. For example, owing to their large surface areas, they offer novel ways at inhibiting protein-protein interactions. As this field has grown, it has become desirable to introduce non-peptidic functionality into these rings to enable differentiated structure activity relationships and improved pharmacokinetic properties. Recent advances in the synthesis of cyclic pseudopeptides include macrocyclization through cysteine alkylation, multicomponent reactions, decarboxylative couplings, and novel stapling chemistry.


Subject(s)
Peptides, Cyclic/chemical synthesis , Alkylation , Carbon/chemistry , Cyclization , Cysteine/chemistry , Peptides, Cyclic/chemistry
5.
J Med Chem ; 59(11): 5403-15, 2016 06 09.
Article in English | MEDLINE | ID: mdl-27148623

ABSTRACT

Our previously reported structures of calpain bound to its endogenous inhibitor calpastatin have motivated the use of aziridine aldehyde-mediated peptide macrocyclization toward the design of cyclic peptides and peptidomimetics as calpain inhibitors. Inspired by nature's hint that a ß-turn loop within calpastatin forms a broad interaction around calpain's active site cysteine, we have constructed and tested a library of 45 peptidic compounds based on this loop sequence. Four molecules have shown reproducibly low micromolar inhibition of calpain-2. Further systematic sequence changes led to the development of probes that displayed increased potency and specificity of inhibition against calpain over other cysteine proteases. Calculated Ki values were in the low micromolar range, rivaling other peptidomimetic calpain inhibitors and presenting an improved selectivity profile against other therapeutically relevant proteases. Competitive and mixed inhibition against calpain-2 was observed, and an allosteric inhibition site on the enzyme was identified for a noncompetitive inhibitor.


Subject(s)
Calpain/antagonists & inhibitors , Drug Design , Glycoproteins/pharmacology , Peptides, Cyclic/pharmacology , Peptidomimetics/pharmacology , Animals , Dose-Response Relationship, Drug , Glycoproteins/chemical synthesis , Glycoproteins/chemistry , Humans , Models, Molecular , Molecular Conformation , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/chemistry , Peptidomimetics/chemical synthesis , Peptidomimetics/chemistry , Rats , Structure-Activity Relationship
6.
J Med Chem ; 59(11): 5368-76, 2016 06 09.
Article in English | MEDLINE | ID: mdl-27120576

ABSTRACT

We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned α to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecular hydrogen bonding network. This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles.


Subject(s)
Amides/chemistry , Macrocyclic Compounds/chemistry , Amides/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Molecular Conformation
7.
Org Biomol Chem ; 13(27): 7384-8, 2015 Jul 21.
Article in English | MEDLINE | ID: mdl-26077966

ABSTRACT

There is an ever-increasing interest in synthetic methods that not only enable peptide macrocyclization, but also facilitate downstream application of the synthesized molecules. We have found that aziridine amides are stereoelectronically attenuated in a macrocyclic environment such that non-specific interactions with biological nucleophiles are reduced or even shut down. The electrophilic reactivity, revealed at high pH, enables peptide sequencing by mass spectrometry, which will further broaden the utility of aziridine amide-containing libraries of macrocycles.


Subject(s)
Amides/chemistry , Electrons , Peptides, Cyclic/chemistry , Sequence Analysis, Protein , Aziridines/chemistry , Hydrolysis , Ketones/chemistry , Mass Spectrometry
8.
Chemistry ; 21(25): 9249-55, 2015 Jun 15.
Article in English | MEDLINE | ID: mdl-26014974

ABSTRACT

The first solid-phase parallel synthesis of macrocyclic peptides using three-component coupling driven by aziridine aldehyde dimers is described. The method supports the synthesis of 9- to 18-membered aziridine-containing macrocycles, which are then functionalized by nucleophilic opening of the aziridine ring. This constitutes a robust approach for the rapid parallel synthesis of macrocyclic peptides.

9.
Methods Mol Biol ; 1248: 67-80, 2015.
Article in English | MEDLINE | ID: mdl-25616326

ABSTRACT

Cyclic peptides have wide utility in the biological sciences. As conformationally locked analogs of the parent linear peptides, they possess greater stability under physiological conditions and increased binding affinity for their targets. As investigations of biological processes often require reporter molecules and functional readouts, chemical probes are commonly appended with functional groups that allow for conjugation to biological entities. Herein we describe the functionalization of cyclic peptides prepared via aziridine aldehyde-mediated macrocyclization. These cyclic peptides contain an aziridine ring that can be further functionalized by ring opening with nucleophiles. We report on the methodology used to produce a cyclic peptide analog of Pro-Gly-Leu-Gly-Phe with either azido or sulfhydryl functionality.


Subject(s)
Oligopeptides/chemistry , Oligopeptides/chemical synthesis , Peptide Library , Peptides, Cyclic/chemistry , Peptides, Cyclic/chemical synthesis
10.
Chem Sci ; 6(10): 5446-5455, 2015 Oct 01.
Article in English | MEDLINE | ID: mdl-29861887

ABSTRACT

Aziridine aldehyde dimers, peptides, and isocyanides participate in a multicomponent reaction to yield peptide macrocycles. We have investigated the selectivity and kinetics of this process and performed a detailed analysis of its chemoselectivity. While the reactants encompass all of the elements of the traditional Ugi four-component condensation, there is a significant deviation from the previously proposed mechanism. Our results provide evidence for an imidoanhydride pathway in peptide macrocyclization and lend justification for the diastereoselectivity and high effective molarity observed in the reaction.

11.
J Org Chem ; 79(21): 9948-57, 2014 Nov 07.
Article in English | MEDLINE | ID: mdl-25254948

ABSTRACT

The factors determining diastereoselectivity observed in the multicomponent conversion of amino acids, aziridine aldehyde dimers, and isocyanides into chiral piperazinones have been investigated. Amino acid-dependent selectivity for either trans- or cis-substituted piperazinone products has been achieved. An experimentally determined diastereoselectivity model for the three-component reaction driven by aziridine aldehyde dimers has predictive value for different substrate classes. Moreover, this model is useful in reconciling the previously reported observations in multicomponent reactions between isocyanides, α-amino acids, and monofunctional aldehydes.


Subject(s)
Aldehydes/chemistry , Amino Acids/chemistry , Aziridines/chemistry , Cyanides/chemistry , Diketopiperazines/chemistry , Molecular Structure , Stereoisomerism
12.
J Org Chem ; 79(20): 9465-71, 2014 Oct 17.
Article in English | MEDLINE | ID: mdl-25264960

ABSTRACT

A multicomponent reaction between an aziridine aldehyde dimer, isocyanide, and l-proline to afford a chiral piperazinone was studied to gain insight into the stereodetermining and rate-limiting steps of the reaction. The stereochemistry of the reaction was found to be determined by isocyanide addition, while the rate-limiting step was found to deviate from traditional isocyanide-based multicomponent reactions. A first-order rate dependence on aziridine aldehyde dimer and a zero-order rate dependence on all other reagents have been obtained. Computations at the MPWPW91/6-31G(d) level supported the experimental kinetic results and provide insight into the overall mechanism and the factors contributing to stereochemical induction. These factors are similar to traditional isocyanide-based multicomponent reactions, such as the Ugi reaction. The computations revealed that selective formation of a Z-iminium ion plays a key role in controlling the stereoselectivity of isocyanide addition, and the carboxylate group of l-proline mediates stereofacial addition. These conclusions are expected to be applicable to a wide range of reported stereoselective Ugi reactions and provide a basis for understanding the related macrocyclization of peptides with aziridine aldehydes.

15.
Chemistry ; 18(49): 15612-7, 2012 Dec 03.
Article in English | MEDLINE | ID: mdl-23124621

ABSTRACT

Bent but not broken: cyclic oligoprolines are accessed in a reaction that effectively bends rigid oligoproline peptides (see scheme; TBDMS=tert-butyldimethylsilyl). The stitching is accomplished during macrocyclization enabled by aziridine aldehydes and isocyanides. Molecular modeling studies suggest that electrostatic attraction between the termini of the linear peptide is pivotal for macrocyclization. The macrocycles were studied by circular dichroism with a polyproline II structure being observed in larger macrocycles.


Subject(s)
Macrocyclic Compounds/chemistry , Oligopeptides/chemistry , Organosilicon Compounds/chemistry , Peptides/chemistry , Circular Dichroism , Cyclization
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