title: Natural-product-like spiroketals and fused bicyclic acetals as potential therapeutic agents for B-cell chronic lymphocytic leukaemia.
abstract: B-cell chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in the Western world for which no curative treatments are currently available. Purine nucleotide analogues and alkylating agents feature frequently in combination regimens to treat the malignant state, but their use has not led to any significant improvement in patient survival. Consequently, there still remains a need for alternative small-molecule chemotherapeutics. Natural products are an unparalleled source of drug leads, and an unending inspiration for the design of small-molecule libraries for drug discovery. The screening of focused libraries of natural-product-like spiroketal and fused bicyclic acetal small molecules against primary CLL cells has led to the identification of a small series of novel and potent cytotoxic agents towards primary CLL cells. The validation of the activity of these molecules is delineated through a series of synthesis and screening iterations, whereas preliminary mode of action studies positively indicate their ability to induce cell death via an apoptotic pathway with no evidence of necrosis to further support their potential as novel chemotherapeutic agents.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB21EW, UK.
authors.forename: Lech-Gustav
authors.initials: LG
authors.lastname: Milroy
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zinzalla
authors.forename: François
authors.initials: F
authors.lastname: Loiseau
authors.forename: Zizheng
authors.initials: Z
authors.lastname: Qian
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Prencipe
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
authors.forename: Steven V
authors.initials: SV
authors.lastname: Ley
mesh_terms: D000080:Acetals / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007928:Lethal Dose 50; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000080:Acetals; D000970:Antineoplastic Agents; D005663:Furans; D013141:Spiro Compounds; C520774:spiroketal; D053148:Caspase 3