Biological Stereoselectivity of Atropisomeric Natural Products and Drugs

Zask, Arie; Murphy, J. S.; Ellestad, George A.

doi:10.1002/chir.22145

Cited by 193 publications

(83 citation statements)

References 48 publications

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“…Abyssomicin C itself has already been comprehensively reviewed by Zask et al and Savic, however its unique atropisomerism necessitates a brief mention here, in the pursuit of expanding recognition of this phenomenon in non-classical systems. 48,49 There were no known inhibitors for this stage of folate synthesis when abyssomicin C was first discovered, hence an assay was devised to screen for any natural compounds which may exhibit activity. Of the actinomycetes screened, only the extracts of Verrucosispora maris strain AB-18-032 showed activity.…”

Section: Abyssomicin C: a Promising Antibacterial For Tuberculosismentioning

confidence: 99%

“…91 Using extensive biogenetic studies, Challis et al determined that the enzyme RedH catalyses the condensation of 2-undecypyrrole (Scheme 9, Compound 47) with 4-methoxy-2,2ʹ-bipyrrole-5-carboxaldehyde (48) to form an acyclic precursor undecylprodigiosin (49), which subsequently undergoes oxidative cyclisation catalysed by RedG to form streptorubin B. 93 The mechanism of this oxidation had recently been determined to proceed through abstraction of the pro-R proton from the C7ʹ position by an Fe(III)OOH complex in the active site of the protein, with inversion of this C7ʹ.…”

Section: Streptorubin B: a Recently Synthesized Antibiotic From Red Pmentioning

confidence: 99%

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A twist of nature – the significance of atropisomers in biological systems

2015

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. (2015). A twist of nature-the significance of atropisomers in biological systems. Natural Product Reports: a journal of current development in bioorganic chemistry, 32 (11), 1562-1583. A twist of nature-the significance of atropisomers in biological systems AbstractRecently identified natural atropisomeric compounds with potential medicinal applications are presented. The ability of natural receptors to possess differential binding between atropisomers is an important factor when considering active and inactive atropisomeric drugs, and has required the development of new techniques for atropselective synthesis of desired targets. Advances in this field therefore have significant relevance to modern pharmaceutical and medicinal chemistry. The atropisomeric natural products discussed include hibarimicinone, flavomannins, talaromannins, viriditoxin, rugulotrosin A, abyssomicin C, marinopyrroles, dixiamycins, streptorubin B, ustiloxins A-F, haouamine A, bisnicalaterines, and tedarene B, all of which show significant potential as leads in antibiotic, antiviral and anticancer studies. The importance for the development of common practices regarding atropisomer recognition and classification is also emphasized. AbstractRecently identified natural atropisomeric compounds with potential medicinal applications are presented. The ability of natural receptors to possess differential binding between atropisomers is an important factor when considering active and inactive atropisomeric drugs, and has required the development of new techniques for atropselective synthesis of desired targets. Advances in this field therefore have significant relevance to modern pharmaceutical and medicinal chemistry. The atropisomeric natural products discussed include hibarimicinone, flavomannins, talaromannins, viriditoxin, rugulotrosin A, abyssomicin C, marinopyrroles, dixiamycins, streptorubin B, ustiloxins A-F, haouamine A, bisnicalaterines, and tedarene B, all of which show significant potential as leads in antibiotic, antiviral and anticancer studies. The importance for the development of common practices regarding atropisomer recognition and classification is also emphasized.

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Section: Abyssomicin C: a Promising Antibacterial For Tuberculosismentioning

confidence: 99%

Section: Streptorubin B: a Recently Synthesized Antibiotic From Red Pmentioning

confidence: 99%

A twist of nature – the significance of atropisomers in biological systems

2015

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“…In one application the asymmetry in an atropisomer is transferred in a chemical reaction to a new stereocenter 6,7,8,9,10 . The atropisomer is an iodoaryl compound synthesised starting from (S)-valine and exists as the (M, S) isomer and the (P, S) isomer.…”

Section: Scopementioning

confidence: 99%

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2014

IJPSR

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When designing small molecules to interact with the targets, one should consider stereo selectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a "coin toss" as to whether or not the "ideal" chiral structure is present. Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid. From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance.

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“…[10] In the cases in which less intuitive molecular fragments leading to conformationalbased chirality are present, numerous analytical tools (NMR, X-ray,chiral HPLC) or even biological assays have been used to determine the existence of atropisomerism. [7,11] Theevaluation of macrocyclic structures as potential drug candidates is currently enjoying asignificant renaissance. [12,13] In particular, these structural motifs are attractive with the perspective of being able to constrain the compound into the binding conformation, and pick up additional protein-ligand interactions.A sp art of our next generation anaplastic lymphoma kinase (ALK) inhibitor project [14] for the treatment of non-small cell lung cancer (NSCLC), we sought to develop as mall molecule inhibitor that combined brain availability with broad-spectrum ALK potencyf or the treatment of patients who exhibit tumor progression while on crizotinib, [15] overcoming resistance mutations [16] and brain metastases.…”

mentioning

confidence: 99%

Conformational Studies and Atropisomerism Kinetics of the ALK Clinical Candidate Lorlatinib (PF‐06463922) and Desmethyl Congeners

et al. 2016

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Lorlatinib (PF-06463922) is an ALK/ROS1 inhibitor and is in clinical trials for the treatment of ALK positive or ROS1 positive NSCLC (i.e. specific subsets of NSCLC). One of the laboratory objectives for this molecule indicated that it would be desirable to advance a molecule which was CNS penetrant in order to treat brain metastases. From this perspective, a macrocyclic template was attractive for a number of reasons. In particular, this template reduces the number of rotatable bonds, provides the potential to shield polar surface area and reinforces binding through a restricted conformation. All of these features led to better permeability for the molecules of interest and thus increased the chance for better blood brain barrier penetration. With a CNS penetrant molecule, kinase selectivity is a key consideration particularly with regard to proteins such as TrkB, which are believed to influence cognitive function. Removal of the chiral benzylic methyl substituent from lorlatinib was perceived as not only a means to simplify synthetic complexity, but also as a strategy to further truncate the molecule of interest. Examination of the NMR of the desmethyl analogues revealed that the compound existed as a mixture of atropisomers, which proved separable by chiral SFC. The individual atropisomers were evaluated through a series of in vitro assays, and shown to have a favorable selectivity profile when compared to lorlatinib. The challenge to develop such a molecule lies in the rate at which the atropisomers interchange dictated by the energy barrier required to do this. Here, we describe the synthesis of the desmethyl macrocycles, conformational studies on the atropisomers, and the kinetics of the interconversion. In addition, the corresponding conformational studies on lorlatinib are reported providing a hypothesis for why a single diastereomer is observed when the chiral benzylic methyl group is introduced.

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Biological Stereoselectivity of Atropisomeric Natural Products and Drugs

Cited by 193 publications

References 48 publications

A twist of nature – the significance of atropisomers in biological systems

A twist of nature – the significance of atropisomers in biological systems

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Conformational Studies and Atropisomerism Kinetics of the ALK Clinical Candidate Lorlatinib (PF‐06463922) and Desmethyl Congeners

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