Ru(II)-Catalyzed Synthesis of Substituted Furans and Their Conversion to Butenolides.

The synthesis of densely functionalized trisubstituted and tetrasubstituted furans via a novel Ru(II)-catalyzed intramolecular cyclization of vinyl diazoesters is reported. The synthetic utility of these furans is further demonstrated through a simple acid-mediated reaction to access highly substituted Δα,ß-butenolides.

Esters of levonorgestrel and etonogestrel intended as single, subcutaneous-injection, long-lasting contraceptives.

An effort with the goal of discovering single-dose, long-lasting (>6 months) injectable contraceptives began using levonorgestrel (LNG)-17-ß esters linked to a sulfonamide function purposed as human carbonic anhydrase II (hCA 2) ligands. One single analog from this first series showed noticeably superior anti-ovulatory activity in murine models, and a subsequent structure-activity relationship (SAR, the relationship between a compound's molecular structure and its biological activity) study based on this compound identified a LNG-phenoxyacetic acid ester analog exhibiting longer anti-ovulatory properties using the murine model at 2 and 4 mg dose than medroxyprogesterone acetate (MPA). The same ester function linked to etonogestrel (ENG) furnished a compound which inhibited ovulation at 2 mg for 60 days, the longest duration of all compounds tested at these doses. By comparison, MPA at the same dose inhibited ovulation for 32 days.

Helenalin Analogues Targeting NF-κB p65: Thiol Reactivity and Cellular Potency Studies of Varied Electrophiles.

Helenalin is a pseudoguaianolide natural product that targets Cys38 within the DNA binding domain of NF-κB transcription factor p65 (RelA). Helenalin contains two Michael acceptors that covalently modify cysteines: a α-methylene-γ-butyrolactone and a cyclopentenone. We recently reported two simplified helenalin analogues that mimic the biological activity of helenalin and contain both electrophilic moieties. To determine the individual contributions of the Michael acceptors toward NF-κB inhibition, we synthesized a small library of helenalin-based analogues containing various combinations of α-methylene-γ-butyrolactones and cyclopentenones. The kinetics of thiol addition to a subset of the analogues was measured to determine the relative thiol reactivities of the embedded electrophiles. Additionally, the cellular NF-κB inhibitory activities of the analogues were determined to elucidate the contributions of each Michael acceptor to biological potency. Our studies suggest the α-methylene-γ-butyrolactone contributes most significantly to the NF-κB inhibition of our simplified helenalin analogues.

A prodrug design for improved oral absorption and reduced hepatic interaction.

A series of estradiol-17-ß esters of N-(p-sulfomylbenzamide)-amino acids were prepared and evaluated for systemic and hepatic estrogenic activity after oral administration in ovariectomized rats. The alkyl substitution at nitrogen of amino acids such as proline or N-methyl-alanine produced compounds that exhibit potent oral activity. The proline analog (EC508) was further evaluated along with 17ß-estradiol (E2) and ethinyl-estradiol (EE) and compared their effects on the uterus, angiotensin and HDL-cholesterol after oral administration to ovariectomized female rats. Orally administered EC508 produced systemic estrogenic activity 10 times greater than EE and a 100 times higher activity than E2 with no influence on levels of angiotensin and HDL-cholesterol, whereas EE and E2 reduced the HDL-cholesterol and increased the angiotensine plasma levels. EC508 might offer significant advantages in indications like fertility control and HRT based on its high oral bioavailability and lack of hepatic estrogenicity.

Synthesis and antileukemic activities of C1-C10-modified parthenolide analogues.

Parthenolide (PTL) is a sesquiterpene lactone natural product with anti-proliferative activity to cancer cells. Selective eradication of leukemic stem cells (LSCs) over healthy hematopoietic stem cells (HSCs) by PTL has been demonstrated in previous studies, which suggests PTL and related molecules may be useful for targeting LSCs. Eradication of LSCs is required for curative therapy. Chemical optimizations of PTL to improve potency and pharmacokinetic parameters have focused largely on the α-methylene-γ-butyrolactone, which is essential for activity. Conversely, we evaluated modifications to the C1-C10 olefin and benchmarked new inhibitors to PTL with respect to inhibitory potency across a panel of cancer cell lines, ability to target drug-resistant acute myeloid leukemia (AML) cells, efficacy for inhibiting clonal growth of AML cells, toxicity to healthy bone marrow cells, and efficiency for promoting intracellular reactive oxygen species (ROS) levels. Cyclopropane 4 was found to possess less toxicity to healthy bone marrow cells, enhanced potency for the induction of cellular ROS, and similar broad-spectrum anti-proliferative activity to cancer cells in comparison to PTL.

Synthesis and characterization of picket porphyrin receptors that bind phosphatidylglycerol, an anionic phospholipid found in bacterial membranes.

The lipid binding ability of four urea-picket porphyrins designed to bind to both the phosphate anion portion as well as the glycerol hydroxyl groups of phosphatidylglycerol (PG) has been investigated. Isothermal titration calorimetry (ITC) and (1)H NMR were used to determine the receptor's stoichiometry of binding, association constants, and both the enthalpy and entropy of binding with the PG anion. Spectral evidence shows that the phosphate anion portion of PG is hydrogen bonded to the urea groups of the receptors. This binding interaction orients the PG anion in the receptor pocket such that its glycerol hydroxyl groups can align with a third urea picket, and results are furnished that suggest this multifunctional interaction does occur. The structure of the entire picket was found to influence the enthalpy and entropy of lipid binding. The synthesis of tetrabutlyammonium phosphatidylglycerol (TBAPG), and a detailed spectral characterization of its headgroup, is also presented.