Novel cytotoxic DNA sequence and minor groove targeted photosensitizers: conjugates of XXXX and @entity73176 analogues.

@entity1 @entity137 @entity6337 @entity35219 @entity19423 @entity5611 @entity26 @entity73176 @entity10918 @entity8304 @entity9435 @entity291 @entity1860
The design, syntheses, photochemical and biological properties of conjugates of @entity9435 with @entity19423 - (1) and @entity8304 -containing (2) analogues of @entity73176 are reported. The results of an @entity5611 displacement assay and circular dichroism (CD) titration studies show both compounds bind with a higher affinity to poly(dA-dT) than to @entity10918 . In addition they bind as strongly to T4 coliphage DNA as to @entity291 thymus DNA suggesting the binding occurs in the minor groove. The quenching rate constants of the singlet excited states of agents 1 and 2 by molecular @entity26 were found to be 8.5 x 10(9) M-1S-1 and 7.7 x 10(9) M-1S-1, suggesting the involvement of singlet @entity26 . Both compounds showed some @entity137 to @entity1 @entity1860 K562 cells in the dark. Upon irradiation the activities were significantly enhanced resulting in photoinduced dose modifications of 8 and 14 for 1 and 2, respectively under the conditions employed. Both agents were markedly more @entity6337 than @entity35219 8. To address the mechanism of action of compounds 1 and 2 their photoactivated abilities to produce DNA strand breaks were measured. Both agents caused increased single strand breakage with increasing UV exposure. The concentrations (EC50) of 1 and 2 needed to cause 50% single-strand cleavage of pBR322 DNA upon UV-A activation were found to be 40 microM and 45 microM, respectively. In contrast, no DNA strand breaks were observed in the dark with either conjugate or with 8 following irradiation. DNA strand breaks were measured in drug treated K562 cells using alkaline elution.(ABSTRACT TRUNCATED AT 250 WORDS)
