Synthesis of Daunorubicin Analogues Containing Truncated Aromatic Cores and Unnatural Monosaccharide Residues

Abstract

The anthracycline antibiotics daunorubicin and doxorubicin have been used widely as anticancer drugs, but their cardiotoxicity limits their clinical use. We describe here the preparation of a small panel of daunorubicin analogues in which the anthraquinone core is replaced with simpler aromatic moieties that lack a quinone functionality. The targets consist of a functionalized 1,2,3,4-tetrahydro-naphthalene or 1,2,3,4-tetrahydro-anthracene core bound to one of three monosaccharides: daunosamine, acosamine, or 4-amino-2,3,6-trideoxy-l-threo-hexopyranose. Key steps in the synthesis included an enantioselective ring opening of benzo-fused norbornene derivatives for the preparation of the core structures and the use of silver hexafluorophosphate-promoted thioglycoside activation in the glycosylation of these cores. Evaluation of these compounds against the MCF-7 cancer cell line demonstrated that the identity of the carbohydrate moiety appeared to have little influence on the cytotoxicity. Moreover, the analogues with the 1,2,3,4-tetrahydro-naphthalene core showed no cytotoxicity, while those possessing the 1,2,3,4-tetrahydro-anthracene moiety were more active. The IC50 values for the latter group of compounds were in the range of 94-134 microM, compared to 17 microM for doxorubicin and 5 microM for daunorubicin.

Does Neighboring Group Participation by Non-Vicinal Esters Play a Role in Glycosylation Reactions? Effective Probes for the Detection of Bridging Intermediates

“…When the acceptor was omitted from the NIS-type activation, the ring-inverted α-glycosyl succinimide 29 was isolated in good yield (Table 4, entry 4) consistent with trapping of the glycosyl oxocarbenium ion being more rapid than any participation by the Boc group. With the 3-azido-2,3,6-trideoxy system 30 , anticipated to undergo more facile ring inversion than 27 and so to have a greater predisposition toward neighboring group participation from the 4-position,38 no cyclic carbonate was found (Table 4, entries 5 and 6). When the activation was conducted without acceptor, only the hydrolysis product was isolated, whereas quenching with cyclohexanol allowed isolation of the glycoside as an anomeric mixture favoring the β-isomer.…”

Palladium-catalyzed ring-opening reactions of cyclopropanated 7-oxabenzonorbornadiene with alcohols

“…Meanwhile, anti- stereoisomeric products 5 and 6 are obtained when copper catalysts are used with alkyl nucleophiles [21], if rhodium [22] or iridium catalysts are used in the presence of heteroatomic nucleophiles [23–24], or when ruthenium catalysts are used with alcohol nucleophiles [25]. Furthermore, unsubstituted dihydronaphthalenols 7 can be obtained through the reductive ring opening of oxabicyclic alkene 1 with hydride nucleophiles [26]. These intermediates find synthetic uses in the preparation of biologically active substances such as arnottin I [27] and sertraline [28].…”

Synthesis and DNA-binding affinity studies of glycosylated intercalators designed as functional mimics of the anthracycline antibiotics

“…The mechanism underlying anthracycline-induced cardiotoxicity is complex, but it is believed that the major cause is the single-electron reduction of ring C (Chart 2) leading to the generation of reactive oxygen species that damage the heart. 8,12 There is no specific treatment for anthracycline-related cardiotoxicity. Thus, new strategies that afford a good therapeutic response with minimal cardiotoxicity are of interest.…”

“…14 Moreover, avoiding cardiotoxicity with compounds containing an anthraquinone or anthraquinone-like portion would be unlikely. 8 It should be noted that analogs of Dauno and Dox containing a truncated anthraquinone core have been prepared; 12,15 however, the cytotoxicity of these simplified analogues is lower than the clinically-used drugs. 12 …”