Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues.

The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki-Hiyama-Kishi coupling to form the C15-C16 carbon-carbon bond, an aldol reaction to construct the C6-C7 carbon-carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose potencies (e.g. IC(50) = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of epothilone B. These investigations led to a number of important structure-activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemistry at both C13 and C15 are crucial for biological activity. These studies also confirmed the importance of both the cyclopropyl and 5-methylpyridine moieties in conferring potent and potentially clinically useful biological properties to the epothilone scaffold.

Recent developments in the chemistry, biology and medicine of the epothilones.

The epothilones have occupied center stage on the scenes of total synthesis, chemical biology and medicine for the last five years, no doubt because of their intriguing mode of action and unusually high potency against tumor cells, including multidrug-resistant cell lines. This article highlights the most recent advances within this exciting field. Thus, an overview of recent synthetic endeavors culminating in a new generation of total syntheses and analogues, some with higher potencies than the naturally occurring substances, will be given, and the chemical biology, in particular the current understanding of structure-activity relationships of the epothilones, will also be discussed in light of the latest biological results. In addition, the recently elucidated biosynthetic machinery of the natural epothilone-producing myxobacterium Sorangium cellulosum, as it is now understood, will be described. Finally, some preclinical and clinical studies will be summarized.

Analysis of missed cases of abusive head trauma.

CONTEXT: Abusive head trauma (AHT) is a dangerous form of child abuse that can be difficult to diagnose in young children. OBJECTIVES: To determine how frequently AHT was previously missed by physicians in a group of abused children with head injuries and to determine factors associated with the unrecognized diagnosis. DESIGN: Retrospective chart review of cases of head trauma presenting between January 1, 1990, and December 31, 1995. SETTING: Academic children's hospital. PATIENTS: One hundred seventy-three children younger than 3 years with head injuries caused by abuse. MAIN OUTCOME MEASURES: Characteristics of head-injured children in whom diagnosis of AHT was unrecognized and the consequences of the missed diagnoses. RESULTS: Fifty-four (31.2%) of 173 abused children with head injuries had been seen by physicians after AHT and the diagnosis was not recognized. The mean time to correct diagnosis among these children was 7 days (range, 0-189 days). Abusive head trauma was more likely to be unrecognized in very young white children from intact families and in children without respiratory compromise or seizures. In 7 of the children with unrecognized AHT, misinterpretation of radiological studies contributed to the delay in diagnosis. Fifteen children (27.8%) were reinjured after the missed diagnosis. Twenty-two (40.7%) experienced medical complications related to the missed diagnosis. Four of 5 deaths in the group with unrecognized AHT might have been prevented by earlier recognition of abuse. CONCLUSION: Although diagnosing head trauma can be difficult in the absence of a history, it is important to consider inflicted head trauma in infants and young children presenting with nonspecific clinical signs.

Lipoprotein-bound bile acids in serum from healthy men, postprandially and during fasting.

Individual bile acids were determined by gas-liquid chromatography in, very low density, low density and high density lipoprotein fractions obtained by sequential ultracentrifugation of serum from normal adults, both postprandially and during fasting. The lipoproteins were found to contain 22-34% of fasting serum bile acids. The observed postprandial increase in bile acids did not exhibit any shift in the ratio between lipoprotein bound- and non-lipoprotein-bound bile acids. Bile acids were present in all isolated lipoprotein fractions, high density lipoproteins containing the highest amounts. In the lipoprotein fraction, a higher percentage of cholate than of chenodeoxycholate was found.