Permanent positive charge strongly influences DNA/RNA binding and antiproliferative activity of urea-phenanthridinium conjugates.
An introduction of the permanent positive charge by methylation of heterocyclic nitrogen on a series of previously studied bis-urea phenanthridine derivatives substantially changed their interactions with DNA and RNA as well as biological activity. At variance to non-methylated analogues, novel methylated derivatives interacted with DNA/RNA not only at pH 5 but also at pH 7, and some compounds switched the DNA binding mode from the minor groove binding (non-methylated derivatives) to the intercalation (novel, methylated derivatives). Moreover, selective ds-RNA over ds-DNA thermal stabilization of previously observed non-methylated derivatives was reversed for novel, methylated derivatives. The variation of a linker length connecting two urea-phenanthridinium conjugates regulated their binding modes toward double stranded polynucleotides. All novel compounds were able to distinguish between polynucleotides of A-T(U) and G-C basepair composition by a specific fluorescence change. Moreover, the introduction of the permanent positive charge on the phenanthridinium moiety resulted in significantly higher biological potency in respect to non-methylated analogues.
Radić Stojković
Marijana
M
Laboratory for Study of Interactions of Biomacromolecules, Ruder Bosković Institute, P.O.B. 180, HR-10002 Zagreb, Croatia.
Marczi
Saska
S
Glavas-Obrovac
Ljubica
L
Piantanida
Ivo
I
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001692:Biological Transport; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D009691:Nucleic Acid Denaturation; D010617:Phenanthridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013696:Temperature; D014508:Urea / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D010617:Phenanthridines; C014740:phenanthridinium; D014867:Water; D012313:RNA; D014508:Urea; D004247:DNA