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

Abstract

Anthracycline antibiotics such as daunomycin (Dauno) and doxorubicin (Dox) are well-known clinically used cancer chemotherapeutics, which, among other mechanisms, bind to DNA, thereby triggering a cascade of biological responses leading to cell death. However, anthracyclines are cardiotoxic, and drug resistance develops rapidly, thus limiting their clinical use. We report here the synthesis and DNA-binding affinity of a novel class of functional anthracycline mimetics consisting of an aromatic moiety linked to a carbohydrate (1–12). In the targets, the aromatic core consists of a 2-phenylbenzo[b]furan-3-yl, 2-phenylbenzo[b]thiophen-3-yl, 1-tosyl-2-phenylindol-3-yl, or 2-phenylindol-3-yl group that is bound to one of three aminosugars (daunosamine, acosamine, or 4-amino-2,3,4,6-tetradeoxy-α-L-hexopyranoside) via a propargyl linker. The DNA binding affinity of these twelve compounds has been evaluated by using both direct and indirect fluorescence measurements. Compared to Dauno and Dox, the DNA binding affinity of these analogues is weaker. However, both aromatic and aminosugar motifs are critical to DNA binding, with more influence coming from the structural features of the aromatic portion.

Total Synthesis of the Postulated Structure of Fulicineroside

“…Compound 53 could also be converted into the cyclic carbonate 55 . The allylic acetate 56 is available by a Ferrier rearrangement of 3,4‐diacetoxy rhamnal 31. Methanolysis of the acetate followed by a Mitsunobu reaction gave the benzoate 57 32.…”

“…The allylic acetate 56 is available by a Ferrier rearrangement of 3,4-diacetoxy rhamnal. [31] Methanolysis of the acetate followed by a Mitsunobu reaction gave the benzoate 57. [32] The latter was converted into the 4-OTBS-protected glycal 58.…”

Applications of Mitsunobu Reaction in total synthesis of natural products

“…Monosaccharide building blocks prepared from Benzyl 2,3‐O‐isopropylidene‐a‐l‐rhamnopyranoside 344 . After several steps, It was transformed into the allylic acetate 345 . Methanolysis of 345 using MeOH and Et 3 N and its treatment with BzOH, DIAD and PPh 3 under Mitsunobu reaction condition give the benzoate 346 .…”

“…[330] After several steps, It was transformed into the allylic acetate 345. [331] Methanolysis of 345 using MeOH and Et 3 N and its treatment with BzOH, DIAD and PPh 3 under Mitsunobu reaction condition give the benzoate 346. [332] The corresponding D -olivose trichloroacetimidate 343 obtained with construction of the hemiacetal 347 from compound 346 in several steps (Scheme 69).…”

Chemical Biology: What is Its Role in Drug Discovery?

“…The anthracycline antibiotics are clinically used cancer chemotherapeutics but drug resistance has become an issue and they are known to be cardiotoxic. With this in mind, a new series of glycosylated anthracycline mimics have been synthesised to overcome these problems (Shi et al, 2009). Synthesis of a range of Nefopam analogues was accomplished in a three-step process .…”