Crystalline guanine adducts of natural and synthetic trioxacarcins suggest a common biological mechanism and reveal a basis for the instability of trioxacarcin A

Pröpper, Kevin; Dittrich, Birger; Smaltz, Daniel J.; Magauer, Thomas; Myers, Andrew G.

doi:10.1016/j.bmcl.2014.08.016

Cited by 6 publications

(3 citation statements)

References 7 publications

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“…Recently, the study of the TXN analog LL-D49194α1 ( 36 ) showed that the deglycosylated compounds ( 37 and 38 ) exhibited more potent anticancer activities than 36, possibly suggesting a new mode of interaction with DNA ( Figure 8 A) [ 47 ]. Furthermore, the DNA–TXN complex ( 39 ) could be cleaved to yield gutingimycin ( 40 ) involving a self-resistance mechanism of an excising base ( Figure 8 B) [ 48 , 49 ]. Recently, four DNA glycosylases, TxnU2, TxnU4, LldU1, and LldU5, were reported to be responsible for excising the intercalated guanine adducts [ 50 ].…”

Section: Dna-alkylating Natural Products With Heterocyclic Propane As...mentioning

confidence: 99%

Biosynthesis of DNA-Alkylating Antitumor Natural Products

Nie

Hou

et al. 2022

Molecules

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DNA-alkylating natural products play an important role in drug development due to their significant antitumor activities. They usually show high affinity with DNA through different mechanisms with the aid of their unique scaffold and highly active functional groups. Therefore, the biosynthesis of these natural products has been extensively studied, especially the construction of their pharmacophores. Meanwhile, their producing strains have evolved corresponding self-resistance strategies to protect themselves. To further promote the functional characterization of their biosynthetic pathways and lay the foundation for the discovery and rational design of DNA alkylating agents, we summarize herein the progress of research into DNA-alkylating antitumor natural products, including their biosynthesis, modes of action, and auto-resistance mechanisms.

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Section: Dna-alkylating Natural Products With Heterocyclic Propane As...mentioning

confidence: 99%

Biosynthesis of DNA-Alkylating Antitumor Natural Products

Nie

Hou

et al. 2022

Molecules

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“…Their mechanism of action as cytotoxic agents involves binding to double-stranded DNA followed by covalent modification of the genetic material through proximity-facilitated nucleophilic attack from a DNA base on the trioxacarcin epoxide moiety. X-ray crystallographic analyses of complexes of trioxacarcin A ( 3 ) (Figure ) , and related compounds with an 8-mer duplex DNA segment or guanine revealed intercalation of the aromatic structural domain of the molecule into DNA. A covalent bond between the N7 atom of a nearby guanine base and the terminal carbon of the spiroepoxide unit formed through nucleophilic attack of the former upon the latter was also observed .…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis of Trioxacarcins DC-45-A1, A, D, C, and C7″-epi-C and Full Structural Assignment of Trioxacarcin C

et al. 2016

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Trioxacarcins DC-45-A2, DC-45-A1, A, D, C7″-epi-C, and C have been synthesized through stereoselective strategies involving BF3·Et2O-catalyzed ketone-epoxide opening and gold-catalyzed glycosylation reactions, and the full structural assignment of trioxacacin C was deciphered via the syntheses of both of its C7″ epimers. The gathered knowledge sets the foundation for the design, synthesis, and biological evalution of analogues of these natural products as potential payloads for antibody-drug conjugates and other delivery systems for targeted and personalized cancer chemotherapy.

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“…Due to the promising potency in anticancer drug development and the complex chemical structure, efforts to obtain analogues by chemical synthesis have continued. − Although much progress has been achieved, processing such a complex architecture is still a challenging task. Recently, biosynthetic studies of TXN-A not only set up the primary biosynthetic pathway but also generated a series of analogues with high antitumor activity. , Herein, the biosynthetic gene cluster (BGC) of LLD was identified and compared with that of TXN-A.…”

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confidence: 99%

Discovery of Druggability-Improved Analogues by Investigation of the LL-D49194α1 Biosynthetic Pathway

et al. 2019

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The biosynthetic gene cluster of antitumor antibiotic LL-D49194α1 (LLD) was identified and comparatively analyzed with that of trioxacarcins. The tailoring genes encoding glycosyltransferase, methyltransferase and cytochrome P450 were systematically deleted, which led to the discovery of eight compounds from the mutants. Preliminary pharmaceutical evaluation revealed two intermediates exhibiting higher cytotoxicity, stability and solubility. These results highlighted the modification pathway for LLD biosynthesis, and provided highly potent, structurally simplified “unnatural” natural products with improved druggability.

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Crystalline guanine adducts of natural and synthetic trioxacarcins suggest a common biological mechanism and reveal a basis for the instability of trioxacarcin A

Cited by 6 publications

References 7 publications

Biosynthesis of DNA-Alkylating Antitumor Natural Products

Biosynthesis of DNA-Alkylating Antitumor Natural Products

Total Synthesis of Trioxacarcins DC-45-A1, A, D, C, and C7″-epi-C and Full Structural Assignment of Trioxacarcin C

Discovery of Druggability-Improved Analogues by Investigation of the LL-D49194α1 Biosynthetic Pathway

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