Symptomatic response to divalproex in subtypes of conduct disorder.

To investigate response to Divalproex sodium (DVPX) with respect to Reactive/Affective/Defensive/Impulsive (RADI) and Proactive/Instrumental/Premeditated (PIP) aggression among adolescent males with conduct disorder (CD), using results from a randomized, double-blind, placebo-controlled trial. It was hypothesized that DVPX response among participants with RADI aggression would be greater than among those with PIP aggression. Fifty-eight ethnically diverse males with severe CD were assigned to High Distress (HDCD) or Low Distress (LDCD) Conduct Disorder, corresponding with RADI and PIP aggression, respectively.

Practice parameter for the assessment and treatment of children and adolescents with oppositional defiant disorder.

Oppositional defiant disorder (ODD) is a common clinical problem in children and adolescents. Oppositionality and associated types of aggressive behavior are among the most common referral problems in child psychiatry. Grouped among the disruptive behavior disorders, ODD is frequently comorbid with other psychiatric conditions and often precedes the development of conduct disorder (CD), substance abuse, and severely delinquent behavior.

Inhibition of c-src transcription by mithramycin: structure-activity relationships of biosynthetically produced mithramycin analogues using the c-src promoter as target.

The aureolic acid antitumor antibiotic mithramycin (MTM) inhibits both cancer growth and bone resorption by cross-linking GC-rich DNA, thus blocking binding of Sp-family transcription factors to gene regulatory elements. Transcription of c-src, a gene implicated in many human cancers and required for osteoclast-dependent bone resorption, is regulated by the binding of Sp factors to specific elements in its promoter. Therefore, this gene represents an important anticancer target and a potential lead target through which MTM displays its so far uncharacterized action against osteoclastic bone resorption.

Mithramycin SK, a novel antitumor drug with improved therapeutic index, mithramycin SA, and demycarosyl-mithramycin SK: three new products generated in the mithramycin producer Streptomyces argillaceus through combinatorial biosynthesis.

To gain initial structure-activity relationships regarding the highly functionalized pentyl side chain attached at C-3 of mithramycin (MTM), we focused on a post-polyketide synthase (post-PKS) tailoring step of the MTM biosynthesis by Streptomyces argillaceus ATCC 12956, which was proposed to be catalyzed by ketoreductase (KR) MtmW. In this last step of the MTM biosynthesis, a keto group of the pentyl side chain is reduced to a secondary alcohol, and we anticipated the generation of an MTM derivative with an additional keto group in the 3-side chain. Insertional inactivation of mtmW, a gene located ca.

Modification of post-PKS tailoring steps through combinatorial biosynthesis.

This review covers the highlights of combinatorial biosynthesis applied on post-polyketide synthase modifying enzymes, such as oxygenases. ketoreductases, glycosyl- and methyltransferases, acyltransferases, halogenases, cyclases and aminotransferases Since this is the first review on this topic, it covers literature from 1985 to 2002, and 248 references are given.

Rationally designed glycosylated premithramycins: hybrid aromatic polyketides using genes from three different biosynthetic pathways.

Heterologous expression of the urdGT2 gene from the urdamycin producer Streptomyces fradiae Tü2717, which encodes a C-glycosyltransferase, into mutants of the mithramycin producer Streptomyces argillaceus, in which either one or all glycosyltransferases were inactivated, yielded four novel C-glycosylated premithramycin-type molecules. Structure elucidation revealed these to be 9-C-olivosylpremithramycinone, 9-C-mycarosylpremithramycinone, and their respective 4-O-demethyl analogues. In another experiment, both the urdGT2 gene from S.

Ketopremithramycins and ketomithramycins, four new aureolic acid-type compounds obtained upon inactivation of two genes involved in the biosynthesis of the deoxysugar moieties of the antitumor drug mithramycin by Streptomyces argillaceus, reveal novel insights into post-PKS tailoring steps of the mithramycin biosynthetic pathway.

Mithramycin is an aureolic acid-type antimicrobial and antitumor agent produced by Streptomyces argillaceus. Modifying post-polyketide synthase (PKS) tailoring enzymes involved in the production of mithramycin is an effective way of gaining further information regarding the late steps of its biosynthetic pathway. In addition, new "unnatural" natural products of the aureolic acid-type class are likely to be produced.

The mtmVUC genes of the mithramycin gene cluster in Streptomyces argillaceus are involved in the biosynthesis of the sugar moieties.

Mithramycin is a glycosylated aromatic polyketide produced by Streptomyces argillaceus, and is used as an antitumor drug. Three genes (mtmV, mtmU and mtmC) from the mithramycin gene cluster have been cloned, and characterized by DNA sequencing and by analysis of the products that accumulate in nonproducing mutants, which were generated by insertional inactivation of these genes. The mtm V gene codes for a 2,3-dehydratase that catalyzes early and common steps in the biosynthesis of the three sugars found in mithramycin (D-olivose, D-oliose and D-mycarose); its inactivation caused the accumulation of the nonglycosylated intermediate premithramycinone.

Characterization of two polyketide methyltransferases involved in the biosynthesis of the antitumor drug mithramycin by Streptomyces argillaceus.

A DNA chromosomal region of Streptomyces argillaceus ATCC 12596, the producer organism of the antitumor polyketide drug mithramycin, was cloned. Sequence analysis of this DNA region, located between four mithramycin glycosyltransferase genes, showed the presence of two genes (mtmMI and mtmMII) whose deduced products resembled S-adenosylmethionine-dependent methyltransferases. By independent insertional inactivation of both genes nonproducing mutants were generated that accumulated different mithramycin biosynthetic intermediates.