The subject of the lecture are water-soluble derivatives of camptothecin,  inhibitors of topoisomerase I, their physical properties and use. These compounds exhibit preferable biological properties, useful in anti-neoplasm therapy. Topoisomerases are important enzymes that convert the chemical energy of molecules with a superhelical structure. These enzymes unwind the DNA double helix weakening the twisting tension of the DNA molecule, making the template accessible to replication or transcription enzymes^{1, 2}.The inhibition of topoisomerase I DNA is thus an important method of fighting cancer using chemotherapy. There are a number of effective bioorganic strategies of use in achieving this goal, such as the non-covalent binding of the poison at the site of degradation,^{8, 11, 12} crosslinking using binding metals,¹³ DNA alkylation^{14, 15} or photochemical DNA damage.¹⁶ Derivatives belonging to the camptothecin family play a significant role, such as Hycamtin^TM or irinotecan, or Camptosar ^TM, are used in clinical treatment as anti-cancer agents. So far, all known derivatives that participate in the inhibition of topo I merely form complexes with the nicked DNA. In conjunction with the abovementioned molecular complex structure, these compounds poorly bind tumour DNA.

There is little data regarding the photochemical transformation using compounds of the camptothecin family (CPT). There is also a lack of other possible mechanisms of the interaction of camptothecin derivatives with tumour DNA. Extant publications concentrate only on the inhibition of the enzyme topo I by way of forming tripartite complexes containing an oligomer of DNA/ topo I /organic ligand. There is thus a large need to deliver a new solution, ensuring the formation of a stable complex using camptothecin derivatives.

The presented data  relates to the synthesis of novel, water-soluble derivatives exhibiting unexpected preferable properties in terms of covalent DNA binding.

References:

[1] Wang, J. C. DNA topoisomerases. Annu. Rev. Biochem. 1996, 65, 635-9

[2] Stewart, L.; Redinbo, M. R.; Qiu, X.; Hol, W. G.; Champoux, J. J. A model for the mechanism of human topoisomerase I. Science 1998, 279, 1534-41.

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