Structure-activity Relationship Profile Research Articles

ChemInform Abstract: Inhibition of DNA Topoisomerase II by Azaelliptitoxins Functionalized in the Variable Substituent Domain.

A series of novel C11-substituted derivatives of azaelliptitoxin (azatoxin) have been synthesized and tested for their inhibitory activity against human DNA topoisomerase II. Incorporation of a C11 polyamine or amine resulted in an increase in the intercalation properties of the drug and a decrease of topoisomerase II activity. The structure-activity relationship (SAR) profile of the nonintercalating C11 anilino azatoxin class follows the SAR of the (anilino)acridine family. 11-(4-Cyanoanilino)azatoxin (14) was found to be the most active analog in this series, exhibiting approximately 10-fold higher activity than azatoxin 12 and etoposide.

Structure-Activity Studies on Antiproliferative Factor (APF) Glycooctapeptide Derivatives.

Antiproliferative factor (APF), a sialylated glycopeptide secreted by explanted bladder epithelial cells from interstitial cystitis/painful bladder syndrome (IC/PBS) patients, and its unsialylated analogue (as-APF) significantly decrease proliferation of bladder epithelial cells and/or certain carcinoma cell lines in vitro. We recently reported a structure-activity relationship profile for the peptide portion of as-APF and revealed that truncation of the C-terminal alanine did not significantly affect antiproliferative activity. To better understand the structural basis for the maintenance of activity of this truncated eight amino acid as-APF (as-APF8), we synthesized several amino acid-substituted derivatives and studied their ability to inhibit bladder epithelial cell proliferation in vitro as well as their solution conformations by CD and NMR spectroscopy. While single amino acid changes to as-APF8 often strongly reduced activity, full potency was retained when the trivaline tail was replaced with three alanines. The Ala(6-8) derivative 9 is the simplest, fully potent APF analogue synthesized to date.

Discovery of the first known small-molecule inhibitors of heme-regulated eukaryotic initiation factor 2α (HRI) kinase

A series of indeno[1,2- c]pyrazoles were discovered to be the first known inhibitors of heme-regulated eukaryotic initiation factor 2α (HRI) kinase. The synthesis, structure–activity relationship profile, and in-vitro pharmacological characterization of this inaugural series of HRI kinase inhibitors are detailed.

Subpicomolar Sensing of δ-Opioid Receptor Ligands by Molecular-Imprinted Polymers Using Plasmon-Waveguide Resonance Spectroscopy

Here we report, for the first time, the formation of a biomimetic covalently imprinted polymeric sensor for a target ligand, the delta-opioid G-protein coupled receptor agonist DPDPE, which reproducibly exhibits subpicomolar binding affinity in an aqueous environment. In addition to having a well-defined and homogeneous binding site, the imprinted polymer template is quite stable to storage in both the dry and wet states and has at least 6 orders of magnitude higher affinities than exhibited by similar peptide-based molecular-imprinted polymers (MIPs) thus far. A highly sensitive optical detection methodology, plasmon-waveguide resonance spectroscopy, was employed, capable of measuring binding in real time and discriminating between ligand molecules, without requiring labeling protocols (fluorophores or radioisotopes). The DPDPE-imprinted polymer showed a broad structure-activity relationship profile, not unlike that found for protein receptors. Such sensitivity and robustness of MIPs suggests potential applications ranging from biowarfare agent detection to pharmaceutical screening.

GABAC RECEPTOR ION CHANNELS

1. The present review gives an overview of studies conducted on GABAC receptors over the past 10 years since the author started at the University of Sydney. It concentrates on the structure-activity relationship profiles of the receptor and how these studies were used to: (i) develop selective GABAC receptor ligands; and (ii) understand the impact of amino acid changes on GABAC receptor pharmacology and function. 2. Structure-activity relationship studies involving variations of both ligands and their receptor targets are vital to the discovery of drugs that interact selectively with particular native and mutant receptor subtypes. Such agents may be useful for treating anxiety, depression, epilepsy and memory related disorders, such as Alzheimer's disease.

Synthetic 1,4-disubstituted 1,4-dihydro-5H-tetrazol-5-one derivatives of fentanyl: Alfentanil (R 39209), a potent, extremely short-acting narcotic analgesic

The synthesis of a series of N-1,4-disubstituted-1,4-dihydro-5H-tetrazol-5-one piperidinyl derivatives of fentanyl, carfentanil, and sufentanil is described. The 1-substituted tetrazolinones 2 were essentially prepared via the addition reaction of aluminium azide to isocyanates or acid chlorides in tetrahydrofuran. Alkylation of 2 under neutral or weakly basic conditions afforded almost exclusively the 1,4-disubstituted tetrazolinone isomer 3. N-Alkylation of the piperidine derivatives 4 with 3 in dimethylformamide yielded 9a-v. The morphinomimetic activity in rats, after intravenous injection of the compounds, was evaluated in the tail withdrawal reflex test. The fentanyl analogues 9a-c (R4 = H) are inactive at the measured dose of 2.5 or 10 mg/kg (iv). For the carfentanil analogues (R4 = COOCH3) maximal narcotic activity is found when R1 represents a lower alkyl group (9d-f) or a thienylethyl group (9n). The sufentanil analogues (R4 = CH2OCH3) show the same structure-activity relationship (SAR) profile as the carfentanil derivatives (R4 = COOCH3). The structural requirements for optimal activity are in good agreement with earlier observations in the series of 10-12. From the series the ethyl tetrazolinone derivative 9r, alfentanil (R 39209), was selected for clinical investigation. As an analgesic in rats, 9r is 140 times more potent than pethidine 15 and 72 times more potent than morphine 14. Alftentanil reaches its peak effect within 1 min after injection, and its duration of action is very short; at 2 times its MED50, 9r has a duration of action of 11 min. This duration is 30 min for 10 and 90 min for 14. Compared to 10, alfentanil 9r is about 4 times faster but 3 times shorter acting. Structurally, 9r shows most resemblance to sufentanil 12, since it differs only by substitution of a 4-ethyltetrazolinone ring for the thiophene ring. The considerable differences in their pharmacological profiles were explained in terms of marked variations in physicochemical and, hence, pharmacokinetic properties.