Natural-Product-Like Spiroketals and Fused Bicyclic Acetals as Potential Therapeutic Agents for B-Cell Chronic Lymphocytic Leukaemia.

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Natural-Product-Like Spiroketals and Fused Bicyclic Acetals as Potential

Therapeutic Agents for B-Cell Chronic Lymphocytic Leukaemia.

Lech-Gustav Milroy, Giovanna Zinzalla, Francois Loiseau, Zizheng Qian, Giuseppe

Prencipe, Pepper, Fegan, and V Ley

ChemMedChem, November 21, 2008; .

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2

1EW (UK), Fax: (+44) 122-333-6442.

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.

PMID: 19025736