Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
Add more filters










Database
Language
Publication year range
1.
Beilstein J Org Chem ; 20: 1320-1326, 2024.
Article in English | MEDLINE | ID: mdl-38887579

ABSTRACT

Eunicellane diterpenoids are a unique family of natural products containing a foundational 6/10-bicyclic framework and can be divided into two main classes, cis and trans, based on the configurations of their ring fusion at C1 and C10. Previous studies on two bacterial diterpene synthases, Bnd4 and AlbS, revealed that these enzymes form cis- and trans-eunicellane skeletons, respectively. Although the structures of these diterpenes only differed in their configuration at a single position, C1, they displayed distinct chemical and thermal reactivities. Here, we used a combination of quantum chemical calculations and chemical transformations to probe their intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the trans-eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization.

2.
J Phys Chem A ; 127(9): 2081-2090, 2023 Mar 09.
Article in English | MEDLINE | ID: mdl-36855831

ABSTRACT

Noncovalent interactions involving sulfur atoms play essential roles in protein structure and function by significantly contributing to protein stability, folding, and biological activity. Sulfur is a highly polarizable atom that can participate in many types of noncovalent interactions including hydrogen bonding, sulfur-π interactions, and S-lone pair interactions, but the impact of these sulfur-based interactions on molecular recognition and drug design is still often underappreciated. Here, we examine, using quantum chemical calculations, the roles of sulfur-based noncovalent interactions in complex naturally occurring molecules representative of thiopeptide antibiotics: glycothiohexide α and its close structural analogue nocathiacin I. While donor-acceptor orbital interactions make only very small contributions, electrostatic and dispersion contributions are predicted to be significant in many cases. In pursuit of understanding the magnitudes and nature of these noncovalent interactions, we made potential structural modifications that could significantly expand the chemical space of effective thiopeptide antibiotics.


Subject(s)
Intercellular Signaling Peptides and Proteins , Sulfur , Sulfur/chemistry , Anti-Bacterial Agents
3.
Chem ; 9(3): 698-708, 2023 Mar 09.
Article in English | MEDLINE | ID: mdl-36937101

ABSTRACT

Terpenoids are the largest family of natural products, but prokaryotes are vastly underrepresented in this chemical space. However, genomics supports vast untapped biosynthetic potential for terpenoids in bacteria. We discovered the first trans-eunicellane terpene synthase (TS), AlbS from Streptomyces albireticuli NRRL B-1670, in nature. Mutagenesis, deuterium labeling studies, and quantum chemical calculations provided extensive support for its cyclization mechanism. In addition, parallel stereospecific labeling studies with Bnd4, a cis-eunicellane TS, revealed a key mechanistic distinction between these two enzymes. AlbS highlights bacteria as a valuable source of novel terpenoids, expands our understanding of the eunicellane family of natural products and the enzymes that biosynthesize them, and provides a model system to address fundamental questions about the chemistry of 6,10-bicyclic ring systems.

4.
Org Biomol Chem ; 21(1): 11-23, 2022 12 21.
Article in English | MEDLINE | ID: mdl-36345987

ABSTRACT

This review discusses the various types of noncovalent interactions in which sulfur atoms participate and their effects on protein stability, structure, folding and bioactivity. Current approaches and recommendations for modelling these noncovalent interactions (in terms of both geometries and interaction energies) are highlighted.


Subject(s)
Sulfur , Hydrogen Bonding , Sulfur/chemistry , Protein Stability
5.
Free Radic Biol Med ; 188: 459-467, 2022 08 01.
Article in English | MEDLINE | ID: mdl-35809768

ABSTRACT

S-Nitrosothiol (RS-NO) generation/levels have been implicated as being important to numerous physiological and pathophysiological processes. As such, the mechanism(s) of their generation and degradation are important factors in determining their biological activity. Along with the effects on the activity of thiol proteins, RS-NOs have also been reported to be reservoirs or storage forms of nitric oxide (NO). That is, it is hypothesized that NO can be released from RS-NO at opportune times to, for example, regulate vascular tone. However, to date there are few established mechanisms that can account for facile NO release from RS-NO. Recent discovery of the biological formation and prevalence of hydropersulfides (RSSH) and their subsequent reaction with RS-NO species provides a possible route for NO release from RS-NO. Herein, it is found that RSSH is capable of reacting with RS-NO to liberate NO and that the analogous reaction using RSH is not nearly as proficient in generating NO. Moreover, computational results support the prevalence of this reaction over other possible competing processes. Finally, results of biological studies of NO-mediated vasorelaxation are consistent with the idea that RS-NO species can be degraded by RSSH to release NO.


Subject(s)
Nitric Oxide , S-Nitrosothiols , Nitric Oxide/metabolism , Proteins/metabolism , Sulfhydryl Compounds
6.
J Am Chem Soc ; 143(24): 9016-9025, 2021 06 23.
Article in English | MEDLINE | ID: mdl-34124896

ABSTRACT

We have developed catalyst-controlled regiodivergent rearrangements of onium-ylides derived from indole substrates. Oxonium ylides formed in situ from substituted indoles selectively undergo [2,3]- and [1,2]-rearrangements in the presence of a rhodium and a copper catalyst, respectively. The combined experimental and density functional theory (DFT) computational studies indicate divergent mechanistic pathways involving a metal-free ylide in the rhodium catalyzed reaction favoring [2,3]-rearrangement, and a metal-coordinated ion-pair in the copper catalyzed [1,2]-rearrangement that recombines in the solvent-cage. The application of our methodology was demonstrated in the first total synthesis of the indole alkaloid (±)-sorazolon B, which enabled the stereochemical reassignment of the natural product. Further functional group transformations of the rearrangement products to generate valuable synthetic intermediates were also demonstrated.


Subject(s)
Copper/chemistry , Indoles/chemical synthesis , Onium Compounds/chemical synthesis , Rhodium/chemistry , Catalysis , Indoles/chemistry , Molecular Structure , Onium Compounds/chemistry
7.
Angew Chem Int Ed Engl ; 59(52): 23772-23781, 2020 12 21.
Article in English | MEDLINE | ID: mdl-32931152

ABSTRACT

Fungal meroterpenoids are a diverse group of hybrid natural products with impressive structural complexity and high potential as drug candidates. In this work, we evaluate the promiscuity of the early structure diversity-generating step in fungal meroterpenoid biosynthetic pathways: the multibond-forming polyene cyclizations catalyzed by the yet poorly understood family of fungal meroterpenoid cyclases. In total, 12 unnatural meroterpenoids were accessed chemoenzymatically using synthetic substrates. Their complex structures were determined by 2D NMR studies as well as crystalline-sponge-based X-ray diffraction analyses. The results obtained revealed a high degree of enzyme promiscuity and experimental results which together with quantum chemical calculations provided a deeper insight into the catalytic activity of this new family of non-canonical, terpene cyclases. The knowledge obtained paves the way to design and engineer artificial pathways towards second generation meroterpenoids with valuable bioactivities based on combinatorial biosynthetic strategies.


Subject(s)
Biosynthetic Pathways/genetics , Fungi/chemistry , Terpenes/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...