Angewandte Chemie International Edition

Cover image for Vol. 55 Issue 7

Chefredakteur: Peter Gölitz, Stellvertreter: Neville Compton, Haymo Ross

Online ISSN: 1521-3773

Associated Title(s): Angewandte Chemie, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemistryOpen, ChemPlusChem, Zeitschrift für Chemie

For full article and contact information, see Angew. Chem. Int. Ed. 2002, 41 (19), 3623 - 3625

No. 19/2002

A Star Brings Hope

A star-shaped molecule may be a weapon
against the resistence of tumors to cytostatic drugs

One of the biggest problems in fighting cancer with chemotherapy is the development of multiple resistance of the tumor; the cancer cells then no longer respond to conventional cytostatic agents. An international team of researchers has now developed a new class of agents that may put an end to the dreaded multiple resistance.

Molecule pumps such as P-glycoprotein play an important role in the development of multiple resistance. Some tumors are able to produce these proteins and incorporate them in their cell membranes when they are tackled with cytostatics. The pumps simply flush the toxic substances back out of the cells -- rendering the cytostatic drugs ineffective. Some molecule-pump inhibitors have previously been discovered; unfortunately these are only effective at concentrations that would unleash dangerous side effects.

A team working with Andreas Hilgeroth at the University of Halle, Germany, Josef Molnar at the University of Szeged, Hungary, and Eric De Clercq at the University of Leuven, Belgium, has now identified an extraordinary class of substances that counteracts multiple resistance in low, nontoxic doses. This was demonstrated in laboratory experiments on strains of cancer cells. The wondrous-sounding name of these unusual substances is diazatetraasterane. To chemists, an asterane is a compound whose core structural element consists of a star-shaped "cage" of carbon atoms (astera = star). A tetraasterane is a "star" with four "points", two of which are formed by nitrogen atoms in the diaza-variation (azote = nitrogen). Various functional groups are bound to the star-shaped framework. The synthetic route used to obtain these compounds forces the functional groups to be placed so as to produce a highly symmetrical structure. The stiff, central cage structure fixes the spatial orientation of the groups, which fit exactly into one of the bindingcavities of the molecule pumps.

Says Hilgeroth, "The inhibitive effect of these highly symmetrical substances could be an indication of a possible, hitherto unrecognized symmetrical construction of the binding site of the molecule pump." Experiments with asymmetrical asteranes should prove this hypothesis. In the meantime, the clinical potential of these new agents is being examined more closely.