Norma Dunlap

Substituents on Etoposide that Interact with Human Topoisomerase IIα in the Binary Enzyme-Drug Complex: Contributions to Etoposide Binding and Activity

Etoposide is a widely prescribed anticancer agent that stabilizes topoisomerase II-mediated DNA strand breaks. The drug contains a polycyclic ring system (rings A-D), a glycosidic moiety at C4, and a pendant ring (E-ring) at C1. A recent study that focused on yeast topoisomerase II demonstrated that the H15 geminal protons of the etoposide A-ring, the H5 and H8 protons of the B-ring, and the H2, H6, 3-methoxyl, and 5-methoxyl protons of the E-ring contact topoisomerase II in the binary enzyme-drug complex [ Wilstermann et al. (2007) Biochemistry 46, 8217-8225 ]. No interactions with the C4 sugar were observed. The present study used DNA cleavage assays, saturation transfer difference [ (1)H] NMR spectroscopy, and enzyme-drug binding studies to further define interactions between etoposide and human topoisomerase IIalpha. Etoposide and three derivatives that lacked the C4 sugar were analyzed. Except for the sugar, 4-demethyl epipodophyllotoxin is identical to etoposide, epipodophyllotoxin contains a 4-methoxyl group on the E-ring, and 6,7- O, O-demethylenepipodophyllotoxin replaces the A-ring with a diol. Results suggest that etoposide-topoisomerase IIalpha binding is driven by interactions with the A- and B-rings and potentially by stacking interactions with the E-ring. We propose that the E-ring pocket on the enzyme is confined, because the addition of bulk to this ring adversely affects drug function. The A- and E-rings do not appear to contact DNA in the enzyme-drug-DNA complex. Conversely, the sugar moiety subtly alters DNA interactions. The identification of etoposide substituents that contact topoisomerase IIalpha in the binary complex has predictive value for drug behavior in the enzyme-etoposide-DNA complex.

A general procedure for a one-pot oxidative cleavage/Wittig reaction of glycols

Abstract Oxidative cleavage of a series of glycols using NaIO4 on silica gel in the presence of a series of stabilized ylides provides access to a number of synthetically useful alkenes. The ease and general utility of this reaction is demonstrated here using several carbohydrates and amino acid derived glycols.

Three-step synthesis of cyclopropyl peptidomimetics.

An efficient approach to novel cyclopropyl peptidomimetics has been developed. The synthetic route involves a cyclopropanation using ethyl (dimethylsulfuranylidene)acetate (EDSA) as the key step and affords a cyclopropyl peptidomimetic core in three steps from protected amino acid Weinreb amides.

Synthesis of Cyclocaric Acid A and Comparison to Material from Cyclocarya paliurus

Components previously reported from Cyclocarya paliurus include the oleananes cyclocaric acids A and B, with cyclocaric acid A possessing an oxetane ring. Isolation of cyclocaric acid A from the plant extract and comparison to the literature report show that the compound originally reported as cyclocaric acid A is, in fact, hederagenin. This was confirmed by independent synthesis of the oxetane and indicates that cyclocaric acid A may not actually be a natural product.

Synthesis and evaluation of ether-linked demethylepipodophyllotoxin dimers

A series of novel ether-linked dimers of demethylepipodophyllotoxin are topoisomerase II poisons that exhibit higher levels of double-stranded versus single-stranded DNA cleavage than their corresponding monomers. The dimers also have higher levels of tumor cell cytotoxicity than the monomers, lending support to the two-drug model for interaction of demethylepipodophyllotoxins with human topoisomerase IIα.

Sterol biosynthesis in the harmful marine dinoflagellate, Karenia brevis: Identification of biosynthetic intermediates produced during exposure to the fungicide fenpropidine

Karenia brevis is a harmful marine dinoflagellate that forms yearly blooms in the Gulf of Mexico. Under normal growth conditions, K. brevis forms two predominant sterols (24R)‐4α‐methyl‐5α‐ergosta‐8(14),22‐dien‐3β‐ol (gymnodinosterol) and its 27‐nor isomer (brevesterol). At the current time, there are no published studies concerning the biosynthesis of these two sterols. We have therefore undertaken experiments in which K. brevis was exposed to the fungicide fenpropidine, an inhibitor of the Δ14‐reductase and the Δ8→7‐isomerase that operate in sterol biosynthesis in both fungal and plant systems. Such exposure to fenpropidine has produced two, tri‐unsaturated intermediates. The identifications of these two K. brevis sterol biosynthesis intermediates, via gas chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy techniques, were 4α‐methyl‐5α‐ergosta‐8,14,22‐trien‐3β‐ol and 5α‐ergosta‐8,14,22‐trien‐3β‐ol.