Differential inhibition of restriction enzyme cleavage by chromophore-modified analogues of the antitumour antibiotics mithramycin and chromomycin reveals structure-activity relationships.
Differential cleavage at three restriction enzyme sites was used to determine the specific binding to DNA of the antitumour antibiotics mithramycin A (MTA), chromomycin A(3) (CRO) and six chromophore-modified analogues bearing shorter side chains attached at C-3, instead of the pentyl chain. All these antibiotics were obtained through combinatorial biosynthesis in the producer organisms. MTA, CRO and their six analogues showed differences in their capacity for inhibiting the rate of cleavage by restriction enzymes that recognize C/G-rich tracts. Changes in DNA melting temperature produced by these molecules were also analyzed, as well as their antiproliferative activities against a panel of colon, ovarian and prostate human carcinoma cell lines. Moreover, the cellular uptake of several analogues was examined to identify whether intracellular retention was related to cytotoxicity. These experimental approaches provided mutually consistent evidence of a seeming correlation between the strength of binding to DNA and the antiproliferative activity of the chromophore-modified molecules. Four of the analogues (mithramycin SK, mithramycin SDK, chromomycin SK and chromomycin SDK) showed promising biological profiles.
Mansilla
Sylvia
S
Instituto de Biologia Molecular de Barcelona, CSIC, Parc Cientific de Barcelona, Baldiri Reixac, Spain.
Garcia-Ferrer
Irene
I
Méndez
Carmen
C
Salas
José A
JA
Portugal
José
J
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D014128:Chromomycin A3 / Q000494:pharmacology; D002865:Chromomycins / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy; D004262:DNA Restriction Enzymes / Q000037:antagonists & inhibitors*; D015252:Deoxyribonucleases, Type II Site-Specific / Q000037:antagonists & inhibitors; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D010051:Ovarian Neoplasms / Q000188:drug therapy; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D002865:Chromomycins; C520007:mithramycin SK; C066851:mithramycin A; D014128:Chromomycin A3; D004262:DNA Restriction Enzymes; C046751:endodeoxyribonuclease XmaIII; D015252:Deoxyribonucleases, Type II Site-Specific; C069035:GACGTC-specific type II deoxyribonucleases; D008926:Plicamycin