Abstract
Crystal structure determination of doxorubicin nitrate, (DoxH)NO3, systematic name (7S,9S)-7-{[(2R,4S,5S,6S)-4-azaniumyl-5-hy-droxy-6-methyl-oxan-2-yl]-oxy}-6,9,11-trihy-droxy-9-(2-hy-droxy-acet-yl)-4-meth-oxy-8,10-di-hydro-7H-tetra-cen-5,12-dione nitrate, shows two formula units present in the asymmetric unit. In the crystal lattice, hydrogen-bonded pairs of (DoxH+) cations and segregation of the aglycone and sugar moieties are observed. Inspection of mol-ecular overlays reveals that the conformation of (DoxH)NO3 resembles that of DNA-inter-calated, but not of protein-docked (DoxH)+. The structure was refined as a two-component twin.
Highlights
Crystal structure determination of doxorubicin nitrate, (DoxH)NO3, systematic name (7S,9S)-7-[(2R,4S,5S,6S)-4-ammonium-5-hydroxy-6-methyloxan-2-yl]oxy6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracen5,12-dione nitrate, shows two formula units present in the asymmetric unit
The anticancer action of doxorubicin is a consequence of its intercalation into base pairs of double-stranded DNA and subsequent inhibition of human DNA topoisomerase II (Arcamone, 1981; Liu, 1989; Chaires, 1998; Yang & Wang, 1999; Jung & Reszka, 2001)
Metal complexation to doxorubicin is known to alter its pharmaceutical activity and several Fe, Mn, Pt and Sn derivatives of the anthracycline have been studied with regard to their anticancer activities (Ming, 2003). (DoxH)+-functionalized iron oxide nanoparticles have been studied as cancer theranostics (Yu et al, 2008)
Summary
Since its discovery and isolation by genetic mutation of Streptomyces peucetius in 1969 (Arcamone et al, 1969), the anthracycline antibiotic doxorubicin [(Dox); trade name adriamycin] has become one of the most potent and widely used drugs in cancer chemotherapy (Denel-Bobrowska & Marczak, 2017; Cagel et al, 2017; Cappetta et al, 2018). Even for daunorubicin ( known as daunomycin), a closely related anthracycline antibiotic, only the crystal structures of its hydrochloride solvates have been reported (Neidle & Taylor, 1977; Courseille et al, 1979). In the absence of a high-resolution crystal structure, researchers have so far relied on computational and solution studies to ascertain the preferred conformational geometry of (Dox) (Zhu et al, 2010; Agrawal et al, 2009; Barthwal et al, 2008). Metal complexation to doxorubicin is known to alter its pharmaceutical activity and several Fe, Mn, Pt and Sn derivatives of the anthracycline have been studied with regard to their anticancer activities (Ming, 2003). We report the 0.80 Aresolution crystal structure determination of doxorubicin nitrate and analyze and compare conformational details
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