Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues

Abstract

The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells. Here we describe syntheses of trioxacarcin A, DC-45-A1, and structural analogs by latestage, stereoselective glycosylation reactions of fully functionalized, differentially protected aglycon substrates. Key issues addressed in this work include the identification of an appropriate means to activate and protect each of the two 2-deoxysugar components, trioxacarcinose A and trioxacarcinose B, as well as a viable sequencing of the glycosidic couplings. The convergent, component-based sequence we present allows for rapid construction of structurally diverse, synthetic analogs that would be inaccessible by any other means, in amounts required to support biological evaluation. Analogs arising from modification of four of five modular components are assembled in 11 steps or fewer. The majority of these are found to be active in antiproliferative assays using cultured human cancer cells.The trioxacarcins are bacterial metabolites of remarkable structural complexity that broadly inhibit the growth of cultured bacterial and eukaryotic cells. [1][2][3][4][5] A number of unusual chemical features characterize the family, including a rigid, highly oxygenated polycyclic skeleton with a fused spiro epoxide function, as many as five ketal or hemiketal groups (three of them within a span of four contiguous carbon atoms) and one or more unusual glycosidic residues, eponymously identified as "trioxacarcinoses". The most potent family member yet identified, trioxacarcin A (Figure 1), displays subnanomolar IC 70 values in a number of different human cancer cell lines. Its extraordinary antiproliferative effects are believed to derive from the fact that trioxacarcin A efficiently and irreversibly alkylates G residues of duplex DNA, forming a covalent bond between the exocyclic carbon atom of the spiro epoxide function and N7 of the G residue that is alkylated. Both the DNA lesion and the product of depurination that is formed from it upon heating, a 1:1 adduct of guanine and Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsCorrespondence and requests for materials should be addressed to A.G.M. * myers@chemistry.harvard.edu Reprints and permission information is available online at http://npg.nature.com/reprintsandpermissions/. Additional information:The authors declare no competing financial interests.Supplementary information and chemical compound information accompany this paper at www.nature.com/naturechemistry. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript trioxacarcin A ("gutingimycin"), 6 have been crystallographically characterized in seminal work from researchers at the University of Göttingen. 7Although so far as we are aware trioxacarcins have...

O-Glycosylation methods in the total synthesis of complex natural glycosides

“…150,151 Attempts to glycosylate the aglycone derivative 155 with a range of trioxacarcinose B donors, including glycosyl uoride, n-pentenyl, and thioglycoside met with failure. This task was fullled with glycosyl acetate 154 as donor and TMSNTf 2 (e.g., 3.3 equiv.)…”

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

“…1), and lacks the trioxacarcinose A glycosyl residue, but is nevertheless a potent cytotoxic agent (GI 50 19 ± 7 nM, H460 cells). 6,7 In this work, we provide evidence that analog 3 also produces DNA lesions by alkylation of guanosine residues within a self-complementary 8-mer duplex DNA, by crystallographic characterization of a 1:1 adduct of 3 and guanine. In addition, we have crystallographically characterized a novel guanine adduct of trioxacarcin A (1), which reveals a heretofore unrecognized pathway for molecular degradation of 1, by elimination of the trioxacarcinose A residue and aromatization/oxidation to form an anthraquinone.…”

“…Incubation of the fully synthetic trioxacarcin analog 3, which lacks one of the carbohydrate residues present in the natural product trioxacarcin A (1) as well as oxygenation at C2 and C4 yet retains potent antiproliferative effects, with the self-complimentary duplex oligonucleotide d(AACCGGTT) led to production of a crystalline covalent guanine adduct (6). Adduct 6 is closely analogous to gutingimycin (2), the previously reported guanine adduct derived from incubation of natural trioxacarcin A (1) with duplex DNA, suggesting that 3 and 1 likely share a common basis of cytotoxicity.…”

“…5 Recently, we reported a fully synthetic, component-based route to trioxacarcin A and used this platform to prepare a number of non-natural trioxacarcin analogs. 6 Many of these analogs were substantially structurally modified relative to trioxacarcin A (1) yet retained potent cytotoxicity. For example, the monoglycoside analog 3 is deoxygenated at the C2-and C4-positions (cf.…”

Diversity-oriented synthesis of Lycopodium alkaloids inspired by the hidden functional group pairing pattern

“…Conceivably, only a small portion of 18 that reacted as in 'path a' might undergo transesterification to produce 14. Through this cascade process, Serratezomine A (1) and two other complex molecules containing tetracyclic skeletons (13,14) were efficiently synthesized in one pot.…”