Diterpenoids of terrestrial origin

Hanson, James R.

doi:10.1039/c4np00108g

Cited by 32 publications

(21 citation statements)

References 190 publications

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“…However, we presume that this compound is also originated from the syn-copalyl carbocation and that a labdane related diterpene with high structural similarity to syn-labda-8(17),12E,14-triene was generated by the ACS mutants. The newly generated diterpenes are of great interest as copalol derivatives display various biological activities analogous to aphidicolin (Hanson, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

Insights Into the Bifunctional Aphidicolan-16-ß-ol Synthase Through Rapid Biomolecular Modeling Approaches

et al. 2018

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Diterpene synthases catalyze complex, multi-step C-C coupling reactions thereby converting the universal, aliphatic precursor geranylgeranyl diphosphate into diverse olefinic macrocylces that form the basis for the structural diversity of the diterpene natural product family. Since catalytically relevant crystal structures of diterpene synthases are scarce, homology based biomolecular modeling techniques offer an alternative route to study the enzyme's reaction mechanism. However, precise identification of catalytically relevant amino acids is challenging since these models require careful preparation and refinement techniques prior to substrate docking studies. Targeted amino acid substitutions in this protein class can initiate premature quenching of the carbocation centered reaction cascade. The structural characterization of those alternative cyclization products allows for elucidation of the cyclization reaction cascade and provides a new source for complex macrocyclic synthons. In this study, new insights into structure and function of the fungal, bifunctional Aphidicolan-16-ß-ol synthase were achieved using a simplified biomolecular modeling strategy. The applied refinement methodologies could rapidly generate a reliable protein-ligand complex, which provides for an accurate in silico identification of catalytically relevant amino acids. Guided by our modeling data, ACS mutations lead to the identification of the catalytically relevant ACS amino acid network I626, T657, Y658, A786, F789, and Y923. Moreover, the ACS amino acid substitutions Y658L and D661A resulted in a premature termination of the cyclization reaction cascade en-route from syn-copalyl diphosphate to Aphidicolan-16-ß-ol. Both ACS mutants generated the diterpene macrocycle syn-copalol and a minor, non-hydroxylated labdane related diterpene, respectively. Our biomolecular modeling and mutational studies suggest that the ACS substrate cyclization occurs in a spatially restricted location of the enzyme's active site and that the geranylgeranyl diphosphate derived pyrophosphate moiety remains in the ACS active site thereby directing the cyclization process. Our cumulative data confirm that amino acids constituting the G-loop of diterpene synthases are involved in the open to the closed, catalytically active enzyme conformation. This study demonstrates that a simple and rapid biomolecular modeling procedure can predict catalytically relevant amino acids. The approach reduces computational and experimental screening efforts for diterpene synthase structure-function analyses.

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Section: Resultsmentioning

confidence: 99%

Insights Into the Bifunctional Aphidicolan-16-ß-ol Synthase Through Rapid Biomolecular Modeling Approaches

et al. 2018

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“…Natural products have played a major role in new drug discovery for centuries, with over 47% of approved anticancer agents being of natural origin [6]. Due to the special structures and diverse biological properties, diterpenoids have attracted much attention of researchers [7]. Plants belonging to Euphorbiaceae families are widely applied in traditional Chinese medicine because these families have rich sources of diterpenoids [8].…”

Section: Introductionmentioning

confidence: 99%

19-(Benzyloxy)-19-oxojolkinolide B (19-BJB), an ent-abietane diterpene diepoxide, inhibits the growth of bladder cancer T24 cells through DNA damage

et al. 2021

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Diterpenoids jolkinolide A and B, were first isolated from Euphorbia fischeriana. In our previous research, 19-(Benzyloxy)-19-oxojolkinolide B (19-BJB), a derivative of jolkinolides, was synthesized as a novel ent -abietane diterpene diepoxide. In this study, 19-BJB showed strong in vitro activity against bladder cancer cell lines. DNA damage which was observed through the interaction of 19-BJB with nucleotide chains and affected DNA repair resulted in the activation of checkpoint kinase 1 (Chk1) and checkpoint kinase 2 (Chk2) in bladder cancer cell lines. In vivo testing in nude mice also proved that 19-BJB revealed a potential inhibitory effect on tumor growth. Additionally, the 3D-QSAR models of jolkinolides were established. Briefly, we proved that 19-BJB could potentially be used as a drug to inhibit the growth of bladder tumor.

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“…Plants are normally an important source of new drugs [2]. In recent years, Isodon genus members have been promising leads due to their extensive pharmacological and physiological effects, such as inhibition of hepatitis viral replication [3] and bacterial infections of the lung or gut [4], as well as its antimalaria [5], antiinflammatory [6], and anti-tumor properties [7]. Hitherto, over 1200 ent -Kaurane-type diterpenoids with highly compact polycyclic ring systems have been isolated from Isodon genus, notably the compounds oridonin [8].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel ent-Kaurane-Type Diterpenoid Derivatives Effective for Highly Aggressive Tumor Cells

et al. 2018

Molecules

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We have designed and synthesized 6 ent-Kaurane-type diterpenoid derivatives containing α,β-unsaturated ketone moieties. In vitro, activity was evaluated against three human tumor cell lines and a rat myogenic cell line (HepG2, NSCLC-H292, SNU-1040, L6) by MTT assay. All the tested compounds exhibited comparable or higher activity than DDP and eriocalyxin B. Compounds 16, 17 and 18 are promising anti-tumor leads due to their cytotoxic potencies and higher selectivity, with SI values of 161.06, 47.80 and 128.20, respectively.

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Diterpenoids of terrestrial origin

Abstract: This review covers the isolation and chemistry of diterpenoids from terrestrial as opposed to marine sources and includes labdanes, clerodanes, abietanes, pimaranes, kauranes, cembranes and their cyclization products. There are 214 references.

Cited by 32 publications

References 190 publications

Insights Into the Bifunctional Aphidicolan-16-ß-ol Synthase Through Rapid Biomolecular Modeling Approaches

Insights Into the Bifunctional Aphidicolan-16-ß-ol Synthase Through Rapid Biomolecular Modeling Approaches

19-(Benzyloxy)-19-oxojolkinolide B (19-BJB), an ent-abietane diterpene diepoxide, inhibits the growth of bladder cancer T24 cells through DNA damage

Synthesis of Novel ent-Kaurane-Type Diterpenoid Derivatives Effective for Highly Aggressive Tumor Cells

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