Pyrrolobenzimidazoles linked to heterocycles and peptides. Design of DNA base pair specific phosphate hydrolyzing agents and novel cytotoxic agents.
Work in this laboratory has been involved with the design of aziridinyl quinone-based cancer drugs (PBIs) capable of both recognizing the DNA major groove and cleaving the phosphate backbone upon reduction to the hydroquinone. The hydroquinone species recognizes the major groove of DNA at single base pairs by Hoogsteen-type hydrogen bonding. The present study extends recognition beyond a single base pair by adding amino acid residues to the 3-amino center of the PBI system. Thus, extension with proline or proline-glycine results in phosphate cleavage at 5'-AA-3' with insignificant N(7) guanine alkylation. Molecular models were used to validate the observed sequence specificity. This report also describes the design of PBIs not capable of DNA alkylation. Removal of major groove interactions by methylation or the presence of steric bulk prevented DNA alkylation reactions upon reductive activation. From these studies it was concluded that DNA alkyation was not necessary for PBI cytostatic and cytotoxic activity. For example, linkage of two phenylalanines to the PBI results in highly selective cytostatic and cytotoxic activity against melanoma, although this compound is a weak DNA alkylator.
Ghodousi
Arman
A
Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, USA.
Huang
Xiaofen
X
Cheng
Zheng
Z
Skibo
Edward B
EB
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry*; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010710:Phosphates / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
C481781:6-aziridinyl-2,3-dihydro-7-methyl-1H-3-(N-phenylalanyl-phenylalanylamino)-pyrrolo(1,2-a)benzimidazole-5,8-dione; C481780:6-aziridinyl-2,3-dihydro-7-methyl-3-(phenylalanylamino)-1H-pyrrolo(1,2-a)benzimidazole-5,8-dione; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D004151:Dipeptides; D010455:Peptides; D010710:Phosphates; D011758:Pyrroles; D010649:Phenylalanine; D004247:DNA