title: Investigating the role of stereochemistry in the activity of anticancer acylfulvenes: synthesis, reductase-mediated bioactivation, and cellular toxicity.
abstract: Acylfulvenes comprise a family of semisynthetic natural product derivatives with potent antitumor activities. Previous studies indicated that acylfulvenes are bioactivated by NADPH-dependent alkenal/one reductase (AOR), presumably generating intermediates with the capacity to alkylate cellular targets, such as DNA, proteins, and glutathione. This process is thought to induce apoptosis, and the chemical and biochemical pathways involved are topics of current investigation. In this study, four acylfulvene analogues were synthesized: (-)-acylfulvene, (+)-acylfulvene, (-)-(hydroxymethyl)acylfulvene, and (+)-(hydroxymethyl)acylfulvene. These compounds were synthesized by a chiral-resolution method, described for the first time in this report, and by asymmetric synthesis using a method formally demonstrated previously. Cell toxicity studies indicate a positive correlation between AOR level and acylfulvene sensitivity. The absolute configuration of acylfulvene analogues has a significant influence on cytotoxicity. (-)-(Hydroxymethyl)acylfulvene is 25 times more potent than (+)-(hydroxymethyl)acylfulvene in cells transfected with an AOR overexpression vector. Based on kinetic parameters, the rates of AOR-mediated activation are more strongly dependent on acylfulvene substitution than on absolute stereochemistry. These data support the role of AOR-mediated metabolism and indicate the involvement of other stereochemically dictated pathways, such as transport and biomolecule binding, in contributing to the cytotoxicity of acylfulvenes.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jiachang
authors.initials: J
authors.lastname: Gong
authors.forename: James F
authors.initials: JF
authors.lastname: Neels
authors.forename: Xiang
authors.initials: X
authors.lastname: Yu
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Peterson
authors.forename: Shana J
authors.initials: SJ
authors.lastname: Sturla
mesh_terms: D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D001711:Biotransformation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D008968:Molecular Conformation; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D013141:Spiro Compounds; C079422:acylfulvene; D000429:Alcohol Oxidoreductases; C082646:leukotriene B4 12-hydroxydehydrogenase