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Conceptually new deltanoids (vitamin D analogs) inhibit multistage skin tumorigenesis
T W Kensler1, P M Dolan, S J Gange
1Department of Environmental Health Sciences and Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA. tkensler@jhsph.edu
Abstract:
Development of vitamin D analogs (deltanoids) as chemopreventive agents requires separation of desirable antiproliferative and pro-differentiating activities from the undesirable calcemic activity also found in the hormone calcitriol (1 alpha, 25-dihydroxyvitamin D(3)). Therefore, several conceptually new deltanoids were synthesized with modifications to the 1alpha- and/or 25-hydroxyl groups, positions traditionally considered essential for stimulating biological responses. In this study, 1 beta-hydroxymethyl-3-epi-25-hydroxyvitamin D(3), a non-calcemic CH(2) homolog of the natural hormone with antiproliferative activity in vitro, was ineffective as an inhibitor of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced induction of ornithine decarboxylase activity in mouse epidermis. However, a hybrid analog incorporating not only the calcemia-ablating 1 beta-hydroxymethyl alteration, but potentiating C,D ring 16-unsaturation and side chain 24,24-fluorination and 26, 27-homologation was found to be as effective as calcitriol. Several non-calcemic 24- or 25-t-butyl sulfones, some containing side chain fluorination but all lacking the 25-hydroxyl group, were also shown to be active in this assay. Three sulfones and the 1 beta-hydroxymethyl hybrid were evaluated as inhibitors of multistage carcinogenesis in mouse skin. Female CD-1 mice were initiated with a single dose of 7,12-dimethylbenz[a]anthracene and then promoted twice weekly for 20 weeks with TPA. Deltanoids were applied topically 30 min before TPA. Unlike calcitriol, none of the atypical deltanoids affected body weight gain in these animals. Minimal effects on urinary calcium excretion were observed following chronic treatment with these analogs. All deltanoids inhibited the incidence and multiplicity of papilloma formation, with the hybrid analog showing the greatest efficacy. With this deltanoid, tumor incidence was significantly reduced by 28% and tumor multiplicity by 63%. These results, coupled with the rich chemical diversity available in side chain sulfur-containing deltanoids, particularly when combined with A ring modifications such as 1 beta-hydroxylalkyl groups, provide important new advances in the fundamental understanding of chemical structure-biological activity relationships as well as more potent and safe vitamin D analogs for cancer chemoprevention and other medicinal uses.
Insights
New vitamin D analogs (deltanoids) show promise for cancer prevention. A novel hybrid deltanoid effectively inhibited tumor formation in mice without causing harmful calcemic activity, offering a safer alternative to calcitriol.
Area of Science:
- Medicinal Chemistry
- Oncology
- Endocrinology
Background:
- Development of vitamin D analogs (deltanoids) aims to separate therapeutic effects from adverse calcemic activity.
- Calcitriol (1 alpha, 25-dihydroxyvitamin D(3)) possesses both beneficial and detrimental properties.
Purpose of the Study:
- To synthesize and evaluate novel deltanoids with modified structures for enhanced chemopreventive efficacy and reduced calcemic effects.
- To assess the in vitro and in vivo activity of these analogs against cancer development.
Main Methods:
- Synthesis of deltanoids with modifications at the 1alpha- and/or 25-hydroxyl groups, including 1 beta-hydroxymethyl and side chain alterations.
- In vitro assessment of antiproliferative activity and inhibition of ornithine decarboxylase induction.
- In vivo evaluation in a mouse skin carcinogenesis model using 7,12-dimethylbenz[a]anthracene initiation and 12-O-tetradecanoylphorbol-13-acetate promotion.
Main Results:
- A hybrid deltanoid with 1 beta-hydroxymethyl alteration, C,D ring unsaturation, and side chain modifications demonstrated potent antiproliferative activity comparable to calcitriol.
- Several non-calcemic sulfone analogs also showed activity in assays.
- In vivo, all tested deltanoids inhibited papilloma formation without affecting body weight or causing significant hypercalcemia. The hybrid analog significantly reduced tumor incidence (28%) and multiplicity (63%).
Conclusions:
- Novel deltanoids, particularly the hybrid analog, offer a promising strategy for cancer chemoprevention with an improved safety profile.
- Structural modifications, including A ring and side chain alterations, are crucial for developing potent and safe vitamin D analogs.
- These findings advance the understanding of structure-activity relationships for vitamin D analogs with potential medicinal applications.