A multiply convergent platform for the synthesis of trioxacarcins

Abstract

Many first-line cancer drugs are natural products or are derived from them by chemical modification. The trioxacarcins are an emerging class of molecules of microbial origin with potent antiproliferative effects, which may derive from their ability to covalently modify duplex DNA. All trioxacarcins appear to be derivatives of a nonglycosylated natural product known as DC-45-A2. To explore the potential of the trioxacarcins for the development of smallmolecule drugs and probes, we have designed a synthetic strategy toward the trioxacarcin scaffold that enables access to both the natural trioxacarcins and nonnatural structural variants. Here, we report a synthetic route to DC-45-A2 from a differentially protected precursor, which in turn is assembled in just six steps from three components of similar structural complexity. The brevity of the sequence arises from strict adherence to a plan in which strategic bond-pair constructions are staged at or near the end of the synthetic route.chemical synthesis | DNA alkylation | anticancer T he trioxacarcins are highly concatenated, densely oxygenated molecules encoded within the genes of various streptomycetes and potently inhibit the growth of cultured human cancer cell lines (1-4). Approximately 20 individual trioxacarcins have been structurally characterized; all appear to be built upon or closely related to the natural product DC-45-A2 (1) (5). The diversity of the trioxacarcin class is well represented by the four compounds that are depicted in Fig. 1 alongside the anthracycline antibiotic daunomycin (daunorubicin, long used in chemotherapy for acute myelogenous leukemias) and nogalamycin, presented in a manner that emphasizes their structural similarities. The trioxacarcins, however, have unique glycosylation patterns, contain a distinct linear aromatic core, and bear as their most distinguishing feature a highly unusual condensed polycyclic trisketal containing a spiro-epoxide. The latter is implicated to be key to the observed antiproliferative effects of the trioxacarcins, for it has been shown to serve as the point of covalent attachment of trioxacarcin A (6-8), the most potent family member in clonogenic assays (4) (with subnanomolar IC 70 values), to G residues of duplex DNA. An X-ray crystallographic analysis of a 2∶1 complex of trioxacarcin A and an 8-mer duplex DNA oligonucleotide (8) reveals that the structure has features related to the (2∶1) nogalamycin-DNA complex (9), with the linear aromatic cores of both small molecules bound intercalatively through the base stack and sugar residues positioned in the major and minor grooves, but unlike nogalamycin, trioxacarcin A covalently modifies the DNA duplex, by reaction of the spiro-epoxide with N7 of a flanking G residue as nucleophile (8). Other structurally distinct natural product families appear to function by pathways that may be mechanistically related (10, 11).To realize their full potential as chemotherapeutic agents and to enable a broader study of the trioxacarcin class of DNA-binding molecules, we ...

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.)…”

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

“…To pursue glycosylation studies we first refined our existing route to the key synthetic precursor 1 , 10 improving the efficiencies of both convergent coupling reactions (as detailed in the Supplementary Information ), and prepared 690 mg of this substance in diastereomerically pure form in a single batch, a >10-fold scaling of our previously published route. The 6-step sequence with current yields is briefly summarized in the first part of Figure 4 below, which depicts the complete route to trioxacarcin A, and is reproduced in order to facilitate discussion of analog synthesis later, where the structures of the initial coupling components are varied.…”

“…As an important first step toward this end in 2011 we reported a six-step route to a differentially protected trioxacarcin aglycon (“synthetic precursor 1 ” in Figure 1 ) by the assembly of three components of similar complexity. 10 We had anticipated that this precursor would serve directly as a substrate for the introduction of carbohydrates such as trioxacarcinose B by glycosylation of the hemiketal hydroxyl group at position C13 or, after cleavage of the p -methoxybenzyl (PMB) ether protective group, would provide a substrate for selective introduction of carbohydrates such as trioxacarcinose A by glycosidation of the hydroxyl group liberated at position C4, which we expected to be more reactive. This expectation was borne out in practice.…”

ChemInform Abstract: Practical Synthesis of p‐ and o‐Amino‐ and Methoxyphenolic Anthraquinones.

“…Examples of such compounds abound and include the biologically active enediynes [1,2] (e.g.u ncialamycin, Figure 1a), [3][4][5][6] tetracycline antibiotics [7] (e.g.v iridicatumtoxin B), [8][9][10] and trioxacarcins [11][12][13][14] (e.g. Examples of such compounds abound and include the biologically active enediynes [1,2] (e.g.u ncialamycin, Figure 1a), [3][4][5][6] tetracycline antibiotics [7] (e.g.v iridicatumtoxin B), [8][9][10] and trioxacarcins [11][12][13][14] (e.g.…”

“…Aminoand methoxy-anthraquinones and related systems are common structural motifs of natural and designed molecules of biological, medical and industrial importance. Examples of such compounds abound and include the biologically active enediynes [1,2] (e.g.u ncialamycin, Figure 1a), [3][4][5][6] tetracycline antibiotics [7] (e.g.v iridicatumtoxin B), [8][9][10] and trioxacarcins [11][12][13][14] (e.g. DC-45-A2) classes of natural products as well as the brightly colorful compounds alizarin and carminic acid (crimson, cochineal).…”