Identification of novel pyrrolopyrazoles as protein kinase C ß II inhibitors.

A novel series of pyrrolopyrazole-based protein kinase C ß II inhibitors has been identified from high-throughput screening. Herein, we report our initial structure-activity relationship studies with a focus on optimizing compound ligand efficiency and physicochemical properties, which has led to potent inhibitors with good cell permeability.

Coordination of Nanoconjugation with an Antigen/Antibody for Efficient Detection of Gynecological Tumors.

Cervical, ovarian, and endometrial cancers are common in the female reproductive system. Cervical cancer starts from the cervix, while ovarian cancer develops when abnormal cells grow in the ovary. Endometrial or uterine cancer starts from the lining of the womb in the endometrium. Approximately 12,000 women are affected every year by cervical cancer in the United States. Squamous cell carcinoma antigen (SCC-Ag) is a well-established biomarker in serum for diagnosing gynecological cancers, and its levels were observed to be elevated in cervical, ovarian, and endometrial cancer patients. Moreover, SCC-Ag was used to identify the tumor size and progression stages. Various biosensing systems have been proposed to identify SCC-Ag; herein, enhanced interdigitated electrode sensing is presented with the use of gold nanoparticles (GNPs) to conjugate an antigen/antibody. It was proved that the limit of detection is 62.5 fM in the case of antibody-GNP, which is 2-fold higher than that by SCC-Ag-GNP. Furthermore, the antibody-GNP-modified surface displays greater current increases with concomitant dose-dependent SCC-Ag levels. High analytical performance was shown by the discrimination against α-fetoprotein and CYFRA 21-1 at 1 pM. An enhanced sensing system is established for gynecological tumors, representing an advance from the earlier detection methods.

Outcome of high-intensity focused ultrasound and uterine artery embolization in the treatment and management of cesarean scar pregnancy: A retrospective study.

The aim of the study was to compare the efficacy and safety between high-intensity focused ultrasound (HIFU) treatment and uterine artery embolization (UAE) treatment; we retrospectively analyzed 152 cases with cesarean scar pregnancy (CSP). Based on our inclusion and exclusion criteria, 152 patients (average age, 31.8 ±â€Š4.6 years old) with CSP were eligible for the HIFU group (85 patients) or the UAE group (77 patients). All patients in 2 groups received the treatment with suction curettage under hysteroscopy prior to HIFU or UAE treatment and followed up for 12 months. The assessment criteria of treatment efficacy included the success rate, intraoperative blood loss, duration of vaginal bleeding, normal menstrual function recovery time, time for ß-human chorionic gonadotrophin (ß-HCG) back to normal level, duration of hospital stays, and other adverse effects. Following up for 12 months, the HIFU group was of less intraoperative blood loss (76.38 ±â€Š22.89 vs 114.42 ±â€Š30.34 mL, P = .02), shorter duration of postoperative vaginal bleeding (11.28 ±â€Š3.65 vs 15.77 ±â€Š7.24 days, P = .01) and lower adverse effects rate comparing to the UAE group. However, the HIFU group have longer time for the ß-HCG recovery to the normal level (35.28 ±â€Š9.86 vs 29.91 ±â€Š7.29, P = .03). Additionally, there were no significantly statistic differences between the 2 groups in baseline characteristics, success rate, and average time of gestational sac disappeared and menstrual recovery and hospital stay. Thus, we concluded that the method of both HIFU and UAE combined with suction curettage under hysteroscopy is safe and effective in the management of CSP. Meanwhile, HIFU is a better therapy option than UAE for those women who are seeking complete relieve of symptom to gain fertility.

Discovery of a novel, orally active, small molecule gonadotropin-releasing hormone (GnRH) receptor antagonist.

Gonadotropin releasing hormone (GnRH) plays an important role in the biology of reproduction. The use of GnRH receptor antagonists has been reported in the literature for the treatment of breast, ovarian, and prostate cancers. In this article, we report the synthesis, in vitro characterization, pharmacokinetics, and pharmacodynamics of an orally bioavailable, potent, small molecule GnRH receptor antagonist N-{4,6-dimethoxy-2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5-yl}-5-[3,3,6-trimthyl-2,3-dihydro-1H-inden-5-yl)oxy]-2-furamide (compound 1).

The discovery of novel small molecule non-peptide gonadotropin releasing hormone (GnRH) receptor antagonists.

A novel series of non-peptide derivatives 1, 14, and 15 that bind with high affinity to the human GnRH receptors is discussed. The discovery was made from screening our in-house libraries that contained the active structure 2 along with a trace amount of a second active structure 1 that was derived from an acid-induced rearrangement. From this structure type 1, a series of guanidine and non-guanidine containing analogues were prepared and tested as GnRH receptor antagonists. Compounds derived from this series bind to both human and rat GnRH receptors and antagonize GnRH-mediated increases in inositol phosphate production in cells containing recombinant human receptors. These compounds or their analogues may be useful as therapeutic agents for the treatment of hormone-dependent pathologies including prostate, breast and ovarian cancers.

Characterization of mono- and diaminopyrimidine derivatives as novel, nonpeptide gonadotropin releasing hormone (GnRH) receptor antagonists.

A novel series of derivatives of mono- and diaminopyrimidines 1 potently displaced binding of a radiolabeled GnRH analogue to human and rat GnRH receptors. Analogues from these series competitively antagonized GnRH-stimulated increases in extracellular acidification in vitro and suppressed GnRH-mediated increases in circulating luteinizing hormone (LH) in castrated rats and testosterone in intact rats. These compounds or their analogues may be useful in treating sex hormone-dependent disease.