Doxorubicin and Aclarubicin: Shuffling Anthracycline Glycans for Improved Anticancer Agents

Abstract

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.

Synthetic (N,N-Dimethyl)doxorubicin Glycosyl Diastereomers to Dissect Modes of Action of Anthracycline Anticancer Drugs

“…Removal of the anomeric p -methoxyphenol group and installation of the alkynylbenzoate was then achieved as described for donors 9 and 12 to give donor 16 . The three alkynylbenzoate donors 9 , 12 , and 16 were used, alongside daunosamine donor 17 that we previously assembled, 13 in glycosylation reactions toward doxorubicin analogues 2b – 3a / b – 4a / b ( Scheme 2 ). Treatment of a mixture of donor 9 and protected doxorubicinone acceptor 18 ( 22 ) with a catalytic amount of PPh 3 AuNTf 2 in DCM at room temperature led to the formation of anthracycline 19 in 80% yield as an 8:1 α/β-mixture.…”

“…13,17 In the assembly of doxorubicin/aclarubicin hybrids, we found that the use of an allyloxycarbamate (Alloc) to mask the amino group of the 2,3-dideoxy-3-aminofucose in combination with relatively labile silyl ethers to protect the hydroxyl groups is very effective for the assembly of the anthracycline targets. 13 Thus, alkynylbenzoate donors 9, 12, and 16 were designed and assembled as depicted in Scheme 1. p-Methoxyphenolates 6 and 10 were prepared from precursor 5 18 (a mixture of 33:67 R/S at C3) by treatment with p-methoxyphenol in the presence of catalytic trimethylsilyl trifluoromethanesulfonate (TMSOTf) to give equatorial azide 6 in 50% yield and axial azide 10 in 7%. Deacylation under Zempleń conditions was followed by triethylsilylation of the resultant alcohol.…”

“…Our follow-up studies on a series of doxorubicin/aclarubicin hybrid structures, varying in the tetracyclic aglycon, the sugar moiety (from the doxorubicin monosaccharide up to the aclarubicin trisaccharide), and the N-alkylation pattern revealed that dimethylated structures fail to induce DNA double-strand breaks while remaining cytotoxic. 13 These findings raise the question whether there is a structure–activity relationship for stereoisomeric analogues of doxorubicin, and whether this may lead to potential new effective anticancer drugs. To this end, we herein report the synthesis and evaluation of a coherent, focused library of diastereomers of doxorubicin ( 1a ) in the 1,2-amino alcohol arrangement of the 3-amino-2,3-dideoxy- l -fucoside (daunosamine) characteristic for this compound.…”

Anthracyclins Increase PUFAs: Potential Implications in ER Stress and Cell Death

“…The sensitivity is conditioned by the mechanism of cell death induced by anthracyclins, which depends on the cell type and drug concentration [ 10 ]. Consequently, understanding this interplay in anthracyclin/lipidome/cell death might open the possibility to: (i) improve diagnosis by biomarkers of the tumor resistance to anthracyclins [ 11 , 12 ], and (ii) propose novel treatments that may potentiate and/or complement the metabolic transformations caused by anthracyclins to induce cell-death.…”

Anthracyclins increase free PUFAs and etherPEs with PUFAs as potential hallmarks of lipid peroxidation and ferroptosis

“…The sensitivity is conditioned by the mechanism of cell death induced by anthracyclins, which depends on the cell type and drug concentration 13 . Consequently, understanding this interplay anthracyclin/lipidome/cell death might open the possibility to: i) improved diagnosis by biomarkers of the tumor resistance to anthracyclins 14,15 , and ii) proposal of novel treatments that may potentiate and/or complement the metabolic transformations caused by anthracyclins to induce cell-death.…”