title: High-affinity inhibitors of dihydrofolate reductase: antimicrobial and anticancer activities of 7,8-dialkyl-1,3-diaminopyrrolo[3,2-f]quinazolines with small molecular size.
abstract: A series of 7,8-dialkylpyrrolo[3,2-f]quinazolines were prepared as inhibitors of dihydrofolate reductase (DHFR). On the basis of an apparent inverse relationship between compound size and antifungal activity, the compounds were designed to be relatively small and compact. Inhibitor design was aided by GRID analysis of the three-dimensional structure of Candida albicans DHFR, which suggested that relatively small, branched alkyl groups at the 7- and 8-positions of the pyrroloquinazoline ring system would provide optimal interactions with a hydrophobic region of the protein. The compounds were potent inhibitors of fungal and human DHFR, with K(i) values as low as 7.1 and 0.1 pM, respectively, and were highly active against C. albicans and an array of tumor cell lines. In contrast to known lipophilic inhibitors of DHFR such as trimetrexate and piritrexim, members of this series of pyrroloquinazolines were not susceptible to P-glycoprotein-mediated multidrug resistance and also showed significant distribution into lung and brain tissue. The compounds were active in lung and brain tumor models and displayed in vivo activity against Pneumocystis carinii and C. albicans.
authors.affiliation: Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Kuyper
authors.forename: D P
authors.initials: DP
authors.lastname: Baccanari
authors.forename: M L
authors.initials: ML
authors.lastname: Jones
authors.forename: R N
authors.initials: RN
authors.lastname: Hunter
authors.forename: R L
authors.initials: RL
authors.lastname: Tansik
authors.forename: S S
authors.initials: SS
authors.lastname: Joyner
authors.forename: C M
authors.initials: CM
authors.lastname: Boytos
authors.forename: S K
authors.initials: SK
authors.lastname: Rudolph
authors.forename: V
authors.initials: V
authors.lastname: Knick
authors.forename: H R
authors.initials: HR
authors.lastname: Wilson
authors.forename: J M
authors.initials: JM
authors.lastname: Caddell
authors.forename: H S
authors.initials: HS
authors.lastname: Friedman
authors.forename: J C
authors.initials: JC
authors.lastname: Comley
authors.forename: J N
authors.initials: JN
authors.lastname: Stables
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects; D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy; D002177:Candidiasis / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000737:chemistry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D008970:Molecular Weight; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy; D017433:Protein Structure, Secondary; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011799:Quinazolines