Anton Stütz

Differential suppression of epidermal antimicrobial protein expression in atopic dermatitis and in EFAD mice by pimecrolimus compared to corticosteroids

Abstract:  It has been suggested that the increased rate of bacterial infection in atopic dermatitis (AD) may be caused by reduced antimicrobial protein (AMP) expression. We were interested whether common treatments in AD affect antimicrobial defense. We investigated the effects of topically applied corticosteroids betamethasone valerate (BV) and triamacinolone acetonide (TA) and those of the calcineurin inhibitor pimecrolimus for 3 weeks on AMP expression in AD. BV and TA treatment in AD led to a significant reduction in AMP expression; protein expression of human beta‐defensins (hBD)‐2 and hBD‐3, psoriasin, RNase 7 and cathelicidin LL‐37 was below the level in skin of healthy controls. After pimecrolimus treatment, AMP expression was also reduced but less compared to BV and TA; the expression levels of hBD‐2, psoriasin and RNase 7 still remained above the control levels. In essential fatty acid–deficient (EFAD) mice, a model of chronic skin barrier disease with inflammation, expression of the mouse beta‐defensins mBD‐1, mBD‐3 and mBD‐14 (orthologues for hBD‐1, hBD‐2 and hBD‐3, respectively), was reduced by both treatments, again more pronounced by BV compared to pimecrolimus. In summary, we found that treatment for AD with corticosteroids in human skin and EFAD mice caused a strong reduction in AMPs; reduction was less with pimecrolimus. This result may explain the clinical observation that prolonged treatment with topical corticosteroids sometimes leads to bacterial infection.

Pharmacological Inhibition of Stearoyl CoA Desaturase in the Skin Induces Atrophy of the Sebaceous Glands

Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the formation of delta9-monounsaturated fatty acids from saturated precursors. Deficiency of SCD-1 in mice causes atrophy of sebaceous glands. We asked whether local pharmacological inhibition of this enzyme in the skin would lead to a similar effect. To this end, we characterized the low-molecular-weight compound XEN103 as a potent and selective inhibitor of SCD-1 activity. The compound blocks microsomal and cellular SCD-1 activity across species with IC50 values in the range of 10-15 nM. Upon topical application to the skin of mice as a 1% solution, XEN103 induces pronounced sebaceous gland atrophy with a rapid onset after a few days of dosing, both sebaceous gland numbers and size being reduced by 50 to 75%, and without any signs of skin irritation. We show that the effect is due to the local action of the compound on SCD-1 in the skin and occurs in the presence of only minimal plasma exposure. Based on these observations, SCD-1 inhibitors such as XEN103 may provide an opportunity to develop a novel topical therapy for acne, as a disease characterized by overproduction of sebum from hypertrophic sebaceous glands.

Regioselective ring opening of α-substituted α-alkynyl oxiranes to 2-substituted 3-butyn-1-ols

Abstract Treatment of α-substituted α-acetylenic epoxides with DIBAH in THF provides 2-substituted 3-butyn-1-ols in high yield avoiding propargyl/allene isomerization.

SDZ 281‐977: A modified partial structure of lavendustin A that exerts potent and selective antiproliferative activities in vitro and in vivo

The chemical derivatization of biologically active microbial metabolites continues to be a promising approach to the identification of new drugs. We recently synthesized the novel antiproliferative compound SDZ 281‐977, 5‐[2‐(2,5‐dimethyoxyphenyl)ethyl]‐2‐hydroxy‐benzoic acid methylester, a derivative of the EGF receptor tyrosine kinase inhibitor lavendustin A. Here we report on our studies of the anticancer efficacy and the mode of action of SDZ 281‐977. The growth of both the human pancreatic tumor cells MIA PaCa‐2 and the human vulvar carcinoma cells A431 was inhibited in the low micromolar range. Tumors from these cells were induced in nude mice and were shown to respond to orally or intravenously administered SDZ 281‐977. In contrast, no antitumor effect was detected in rats bearing dimethylbenzanthracene‐induced mammary tumors. Studies in mice indicated that SDZ 281‐977 was neither immunosuppressive nor hematosuppressive at doses effectively inhibiting tumor growth. Surprisingly, the mode of action of SDZ 281‐977 apparently does not involve inhibition of EGF receptor tyrosine kinase, because, in contrast to lavendustin A, SDZ 281‐977 failed to inhibit this enzyme in a cell‐free assay. The mechanism of the antiproliferative effect can be explained on a cellular level by the ability of the compound to arrest cells in mitosis. SDZ 281‐977 is thus the first example of an antimitotic agent derived from the potent tyrosine kinase inhibitor lavendustin A. The therapeutic potential of SDZ 281‐977 is enhanced by the fact that it is not subject to multidrug resistance, because tumor cells expressing the multidrug resistance phenotype were as sensitive to SDZ 281‐977 as their nonresistant counterparts. In conclusion, SDZ 281‐977 represents a novel lavendustin A derivative with potent antiproliferative properties in vitro and in vivo that may be explained on the basis of its antimitotic effects. SDZ 281‐977 may be a candidate drug for the treatment of selected cancers, including those expressing the multidrug resistance phenotype.