11002-83-8Relevant articles and documents
Characterization of rhodosaminyl transfer by the AknS/AknT glycosylation complex and its use in reconstituting the biosynthetic pathway of aclacinomycin A
Leimkuhler, Catherine,Fridman, Micha,Lupoli, Tania,Walker, Suzanne,Walsh, Christopher T.,Kahne, Daniel
, p. 10546 - 10550 (2007)
The tetracyclic core of anthracycline natural products with antitumor activity such as aclacinomycin A are tailored during biosynthesis by regioselective glycosylation. We report the first synthesis of TDP-L-rhodosamine and demonstrate that the glycosyltransferase AknS transfers L-rhodosamine to the aglycone to initiate construction of the side-chain trisaccharide. The partner protein AknT accelerates AknS turnover rate for L-rhodosamine transfer by 200-fold. AknT does not affect the Km but rather affects the kcat. Using these data, we propose that AknT causes a conformational change in AknS that stabilizes the transition state and ultimately enhances transfer. When the subsequent glycosyltransferase AknK and its substrate TDP-L-fucose are also added to the aglycone, the disaccharide and low levels of a fully reconstituted trisaccharide form of aclacinomycin are observed.
Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents
Wander, Dennis P. A.,Van Der Zanden, Sabina Y.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.,Neefjes, Jacques,Codée, Jeroen D. C.
, p. 12814 - 12829 (2020/11/17)
Anthracycline anticancer drugs doxorubicin and aclarubicin have been used in the clinic for several decades to treat various cancers. Although closely related structures, their molecular mode of action diverges, which is reflected in their biological activity profile. For a better understanding of the structure-function relationship of these drugs, we synthesized ten doxorubicin/aclarubicin hybrids varying in three distinct features: Aglycon, glycan, and amine substitution pattern. We continued to evaluate their capacity to induce DNA breaks, histone eviction, and relocated topoisomerase IIα in living cells. Furthermore, we assessed their cytotoxicity in various human tumor cell lines. Our findings underscore that histone eviction alone, rather than DNA breaks, contributes strongly to the overall cytotoxicity of anthracyclines, and structures containing N,N-dimethylamine at the reducing sugar prove that are more cytotoxic than their nonmethylated counterparts. This structural information will support further development of novel anthracycline variants with improved anticancer activity.
Antitumor anthracycline antibiotics, aclacinomycin A and analogues. II. Structural determination
Oki,Kitamura,Matsuzawa,Shibamoto,Ogasawara,Yoshimoto,Inui,Naganawa,Takeuchi,Umezawa
, p. 801 - 819 (2007/10/10)
The structures of aclacinomycins A and B and 19 analogues were determined by a combination of chemical conversions and degradations and spectral interpretations.
