Regio- and diastereoselective synthesis and X-ray structure determination of (+)-2-deoxyoryzalexin S from (+)-podocarpic acid. Structural nonidentity with its nominal natural isolated enantiomer.

(+)-2-Deoxyoryzalexin S (1), the nominal enantiomer of a diterpenoid isolated in Chile from Calceolaria species, was regio- and diastereoselectively synthesized from (+)-podocarpic acid. (+)-2-Deoxyoryzalexin S (1) was characterized also as its acetyl derivative, (+)-2, whose structure was confirmed by X-ray crystallographic analysis. Surprisingly, comparison of the data recorded for (+)-1 and (+)-2 and those reported in the literature for the Calceolaria isolated diterpenoid 1 and its derivative (-)-2 showed some differences, suggesting that the latter do not possess the proposed structures.

Design, synthesis and applications of hyaluronic acid-paclitaxel bioconjugates.

Paclitaxel (1a), a well known antitumor agent adopted mainly for the treatment of breast and ovarian cancer, suffers from significant disadvantages such as low solubility, certain toxicity and specific drug-resistance of some tumor cells. To overcome these problems extensive research has been carried out. Among the various proposed strategies, the conjugation of paclitaxel (1a) to a biocompatible polymer, such as hyaluronic acid (HA, 2), has also been considered. Coupling a bioactive compound to a biocompatible polymer offers, in general, many advantages such as better drug solubilization, better stabilization, specific localization and controlled release. Hereafter the design, synthesis and applications of hyaluronic acid-paclitaxel bioconjugates are reviewed. An overview of HA-paclitaxel combinations is also given.

Targeting Serotonin 2A and Adrenergic α1 Receptors for Ocular Antihypertensive Agents: Discovery of 3,4-Dihydropyrazino[1,2-b]indazol-1(2H)-one Derivatives.

Glaucoma affects millions of people worldwide and causes optic nerve damage and blindness. The elevation of the intraocular pressure (IOP) is the main risk factor associated with this pathology, and decreasing IOP is the key therapeutic target of current pharmacological treatments. As potential ocular hypotensive agents, we studied compounds that act on two receptors (serotonin 2A and adrenergic α1 ) linked to the regulation of aqueous humour dynamics. Herein we describe the design, synthesis, and pharmacological profiling of a series of novel bicyclic and tricyclic N2-alkyl-indazole-amide derivatives. This study identified a 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one derivative with potent serotonin 2A receptor antagonism, >100-fold selectivity over other serotonin subtype receptors, and high affinity for the α1 receptor. Moreover, upon local administration, this compound showed superior ocular hypotensive action in vivo relative to the clinically used reference compound timolol.

Novel Locally Active Estrogens Accelerate Cutaneous Wound Healing-Part 2.

Estrogen deprivation is associated with delayed healing, while estrogen replacement therapy (ERT) accelerates acute wound healing and protects against development of chronic wounds. However, current estrogenic molecules have undesired systemic effects, thus the aim of our studies is to generate new molecules for topic administration that are devoid of systemic effects. Following a preliminary study, the new 17ß-estradiol derivatives 1 were synthesized. The estrogenic activity of these novel compounds was evaluated in vitro using the cell line ERE-Luc B17 stably transfected with an ERE-Luc reporter. Among the 17ß-estradiol derivatives synthesized, compounds 1e and 1f showed the highest transactivation potency and were therefore selected for the study of their systemic estrogenic activity. The study of these compounds in the ERE-Luc mouse model demonstrated that both compounds lack systemic effects when administered in the wound area. Furthermore, wound-healing experiments showed that 1e displays a significant regenerative and anti-inflammatory activity. It is therefore confirmed that this class of compounds are suitable for topical administration and have a clear beneficial effect on wound healing.

Gabapentin treatment of neurogenic overactive bladder.

OBJECTIVE: Detrusor overactivity is a well-recognized and distressing medical condition affecting both men and women, with a significant prevalence in the population and with a higher incidence rate in people older than 70 years. This pathological condition is characterized by irritative symptoms: urinary urgency, with or without incontinence, and urinary frequency, often seriously compromising the quality of life of the people who have it. The complaint of these symptoms is defined by the International Continence Society (www.continet.org) as "overactive bladder." Many neurological patients experience irritative symptoms of the lower urinary tract related to their disease, and this condition drastically limits their social life. Various drugs have been introduced in therapy protocols to treat neurogenic detrusor overactivity; however, in many cases, the outcomes of these treatments have proven to be unsatisfactory. This fact is probably related to the incomplete understanding of the pathophysiological aspects of detrusor overactivity. Recent studies suggest the possible role in the detrusor overactivity pathogenesis of bladder receptors, afferent pathways, and spinal cord interneurons; consequently, the modulation of bladder receptor and/or spinal cord centers activity has been proposed as a possible approach to control involuntary detrusor contractions, using drugs capable of acting on bladder afferent pathways. The aim of this study was to evaluate the efficacy of gabapentin, an anticonvulsive agent used by neurologists in the treatment of epilepsy and neurogenic pain, in the treatment of detrusor overactivity of neurogenic origin. METHODS: Sixteen patients affected by neurogenic overactive bladder were enrolled in the study. The clinical outcomes were assessed by symptomatic score evaluations, voiding diary, and urodynamic test before and after 31 days of gabapentin treatment. RESULTS: The preliminary results showed significant modifications of urodynamic indexes, particularly of the detrusor overactivity, whereas the symptomatic score evaluation and the voiding diary data demonstrated a significant lowering of the irritative symptoms. Furthermore, we did not record significant adverse effects and no patient interrupted the drug treatment. CONCLUSIONS: These data support the rationale that detrusor overactivity may be controlled by modulating the afferent input from the bladder and the excitability of the sacral reflex center and suggest a novel method to treat overactive bladder patients.

Novel locally active estrogens accelerate cutaneous wound healing. A preliminary study.

New 17beta-estradiol (E2) derivatives 1-11 were synthesized from an estrone derivative by addition of organometallic reagents prepared from protected alpha,omega-alkynols and further elaboration of the addition products. The estrogenic activity of these novel compounds was determined using in vitro binding competition assay and transactivation analysis. Among the E2 derivatives synthesized, compound 2 showed the highest transactivation potency and was therefore tested for its ability to modulate cutaneous wound healing in vivo. Compound 2's ability to accelerate wound healing in ovariectomized mice and decrease the production of inflammatory molecules was comparable to that of E2. However, the activity of compound 2 was not superimposable to E2 with regard to the cells involved in the wound repairing process. When locally administered, compound 2 did not show any systemic activity on ER. This class of compounds with clear beneficial effects on wound healing and suitable for topical administration may lead to the generation of innovative drugs for an area of unmet clinical need.