Natural-product-like spiroketals and fused bicyclic acetals as potential therapeutic agents for B-cell chronic lymphocytic leukaemia.
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.
Milroy
Lech-Gustav
LG
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB21EW, UK.
Zinzalla
Giovanna
G
Loiseau
François
F
Qian
Zizheng
Z
Prencipe
Giuseppe
G
Pepper
Chris
C
Fegan
Chris
C
Ley
Steven V
SV
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
D000080:Acetals; D000970:Antineoplastic Agents; D005663:Furans; D013141:Spiro Compounds; C520774:spiroketal; D053148:Caspase 3