A Novel, “Double-Clamp” Binding Mode for Human Heme Oxygenase-1 Inhibition

The development of heme oxygenase (HO) inhibitors is critical in dissecting and understanding the HO system and for potential therapeutic applications. We have established a program to design and optimize HO inhibitors using structure-activity relationships in conjunction with X-ray crystallographic analyses. One of our previous complex crystal structures revealed a putative secondary hydrophobic binding pocket which could be exploited for a new design strategy by introducing a functional group that would fit into this potential site. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have synthesized and characterized 1-(1H-imidazol-1-yl)-4,4-diphenyl-2-butanone (QC-308). Using a carbon monoxide (CO) formation assay on rat spleen microsomes, the compound was found to be ∼15 times more potent (IC50 = 0.27±0.07 µM) than its monophenyl analogue, which is already a potent compound in its own right (QC-65; IC50 = 4.0±1.8 µM). The crystal structure of hHO-1 with QC-308 revealed that the second phenyl group in the western region of the compound is indeed accommodated by a definitive secondary proximal hydrophobic pocket. Thus, the two phenyl moieties are each stabilized by distinct hydrophobic pockets. This “double-clamp” binding offers additional inhibitor stabilization and provides a new route for improvement of human heme oxygenase inhibitors

Gynecologic oncology group trials of chemotherapy for metastatic and recurrent cervical cancer

Because only 16% of patients with metastatic cervical cancer are alive 5 years after diagnosis, the Gynecologic Oncology Group (GOG) has carefully designed and conducted many phase II studies to identify promising drugs. Cisplatin has emerged as the most active single agent with overall response rates of 19%. Recent phase III trials have documented response rates of 27% and 39% when cisplatin has been combined with either paclitaxel or topotecan, respectively. The comparison of cisplatin to cisplatin plus topotecan in GOG-179 has yielded the first study to show a statistically significant impact on the overall response rate, median progression-free survival, and median survival, with all outcome measures favoring the two-drug regimen. Despite these encouraging results, however, most of the responses are partial and of short duration. The need for novel combinations and the implementation of active biologic agents is implicit. The accumulated data in this disease setting, as evidenced by the experience of the GOG, are presented in this review

Some reproductive traits of the Tristan klipfish, Bovichtus diacanthus (Carmichael 1819) (Notothenioidei: Bovichtidae) from Tristan da Cunha (South Atlantic)

The reproductive biology of the Tristan klipfish, Bovichtus diacanthus, was investigated by macroscopic and histological analyses of the gonads. Fish samples were collected in tide pools at Tristan da Cunha in July 2004. Most specimens of both sexes were developing, or sexually mature, with a gonadosomatic index (GSI) of 7.0-9.2% in females and 0.2-0.6% in males. Histologically, testes showed a random distribution of spermatogonia along the lobules, a condition defined as the unrestricted spermatogonial type. Ripe males exhibited lobules with all spermatogenic stages of development from spermatogonia to spermatozoa. In mature females, the ovarian follicles consisted of three main cohorts of oocytes of different sizes; the smaller one represented by previtellogenic oocytes of 15-150 mu m and the other two by yolked oocytes measuring, respectively, 300-1000 and 800-1500 mu m. The overlap between the stock of advanced yolked oocytes and the early yolked oocytes was low, decreasing progressively with final maturation. As a result, B. diacanthus was considered a batch spawner, with a spawning season extending from July to August onward. Batch fecundity, based on the most advanced yolked oocytes, was 2,047-8,317 mature oocytes/female, whereas the relative fecundity was 77-141 mature oocytes/g. In the light of the phyletically basal position of bovichtids in the suborder, the reproductive traits of B. diacanthus were compared with those previously described in other Antarctic and non-Antarctic notothenioids