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SANTA CLARA, CA, United States

Gobis K.,Medical University of Gdansk | Foks H.,Medical University of Gdansk | Bojanowski K.,Sunny Biodiscovery, Inc. | Augustynowicz-Kopec E.,Institute of Tuberculosis and Pulmonary Diseases | Napiorkowska A.,Institute of Tuberculosis and Pulmonary Diseases
Bioorganic and Medicinal Chemistry | Year: 2012

A series of novel 3-cyclohexylpropanoic acid derivatives and 3-cyclohexylpropanoic acid-derived nitrogen heterocyclic compounds (1-8) have been synthesized and evaluated for tuberculostatic activity. Compounds 1a, 1c, 1e and 1f bearing benzimidazole or benzimidazole-like systems showed the most potent tuberculostatic activity against Mycobacterium tuberculosis strains with MIC values ranging from 1.5 to 12.5 μg/mL. More importantly 1a (6-chloro-2-(2-cyclohexylethyl)-4-nitro-1H-benzo[d]imidazole) and 1f (2-(2-cyclohexylethyl)-1H-imidazo[4,5-b]phenazine) appeared selective for M. tuberculosis as compared with eukaryotic cells (human fibroblasts), and other antimicrobial strains. These compounds may thus represent a novel, selective class of antitubercular agents. Additionally compound 1a stimulated type I collagen output by fibroblasts, in vitro. © 2011 Elsevier Ltd. All rights reserved.

Chaudhuri R.K.,Sytheon Ltd. | Bojanowski K.,Sunny Biodiscovery, Inc.
International Journal of Cosmetic Science | Year: 2014

Synopsis Objective The study was undertaken to compare the skin care related activities of retinol and bakuchiol, a potential alternative to retinoids. Retinol is a pivotal regulator of differentiation and growth of developing as well as adult skin. Retinoic acid is the major physiologically active metabolite of retinol regulating gene expression through retinoic acid receptor - dependant and independent pathways. Methods Comparative gene expression profiling of both substances in the EpiDerm FT full thickness skin substitute model was undertaken. Furthermore, type I, III and IV collagen, as well as aquaporin 3 expression was analyzed by ELISA and/or histochemistry in human dermal fibroblasts and/or Epiderm FT skin substitutes. Results Bakuchiol is a meroterpene phenol abundant in seeds and leaves of the plant Psoralea corylifolia. We present evidence that bakuchiol, having no structural resemblance to retinoids, can function as a functional analogue of retinol. Volcano plots showed great overall similarity of retinol and bakuchiol effects on the gene expression profile. This similarity was confirmed by the side-by-side comparison of the modulation of individual genes, as well as on the protein level by ELISA and histochemistry. Retinol-like functionality was further confirmed for the upregulation of types I and IV collagen in DNA microarray study and also show stimulation of type III collagen in the mature fibroblast model. Bakuchiol was also formulated into a finished skin care product and was tested in clinical case study by twice-a-day facial application. The results showed that, after 12 weeks treatment, significant improvement in lines and wrinkles, pigmentation, elasticity, firmness and overall reduction in photo-damage was observed, without usual retinol therapy-associated undesirable effects. Conclusion Based on these data, we propose that bakuchiol can function as an anti-ageing compound through retinol-like regulation of gene expression. A comparative gene expression profiling between retinol and bakuchiol revealed retinol-like functional properties of bakuchiol. © 2014 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Bojanowski K.,Sunny Biodiscovery, Inc.
International Journal of Cosmetic Science | Year: 2013

Synopsis Objective Skin compartments traditionally targeted by cosmetic actives - epidermis and dermis - are anchored and nourished by the underlying hypodermis, which therefore should be a key target for skin-rejuvenating formulations. However, given the difficulty to reach even the superficial layers of the skin, and to its 'unglamorous' fatty composition, the regenerative potential of hypodermis remains largely untapped. Therefore, this study was to investigate the capacity of a cosmetic material to trigger a regenerative response in dermis and epidermis through a selective action on hypodermis. Furthermore, it aimed to establish the effect of such cosmetic material in transbuccal hypodermal delivery form, on the hypodermal precursor cells - the preadipocytes. Methods A combination of grape seed extract and soy phospholipids was formulated and standardized for elastase activity and free radical inhibition. This formulation was then used to contact the hypodermal layer of human skin biopsies and - under a transbuccal delivery vehicle form - the 3T3-L1 preadipocytes, and its effects were quantified using PCR arrays and histochemistry. Results Application of the standardized grape/soy material to the hypodermal layer of skin triggered modulation of gene expression in the upper layers of the skin and resulted in the clear morphological improvement at the dermal and epidermal levels. Furthermore, when this material was formulated in a mucoadhesive, intraoral film and applied on 3T3-L1 preadipocytes, the resulting modulation of gene expression in these cells was consistent with differentiation and detoxification effects. Conclusions These results suggest that transbuccal formulations of nutraceutical grade cosmetics have potential to induce signal transduction pathways in facial hypodermis, resulting in anti-aging effects throughout all skin compartments, including dermal and epidermal layers. © 2013 Society of Cosmetic Scientists and the Societe Francaise de Cosmetologie.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 227.62K | Year: 2002

Inhibition of tumor angiogenesis-the growth of new blood vessels towards the tumor mass-is a new and promising approach to anti-cancer therapy. The results of Phase I/II clinical trials completed so far with several angiogenesis inhibitors validate the concept of tumor angiogenesis as effective target for anti-cancer therapy. However, the same studies stress the need for novel, more potent angiogenesis inhibitors. We addressed this need by isolating the human urine a new protein (SBD.1), which specifically blocks the proliferation of capillary endothelial cells in vitro (ID50=15NG/ML), angiogenesis in chorioallentoic membrane assay, and two growth in vivo (Lewis Lung Carcinoma, T/C=0.04 at 20umum/kg/day), placing SBD.1 among the most potent known angiogenesis inhibitors. Sequencing of SBD/1 showed it is a novel protein and its mild proteolysis resulted in the generation of smaller peptides without losing the inhibitory activity. Here, we propose to a) clone and express SBD.1 in a recombinant system; b) isolate and sequence the activity SBD.1 fragments; c) test the purified SBD.1 on prostate, lung and breast carcinoma human xenografts in nude mice to further assess its anti-tumor activity This project will result in the cloning of a novel therapeutically-active protein, which may be an important endogenous regulator of angio- and tumorigenesis in humans. PROPOSED COMMERCIAL APPLICATIONS: The development of SBD.1 addresses a pressing need in the pharmaceutical industry for a new, better angiogenesis inhibitor. Currently targeting anti-cancer therapy, the use of SBD.1 might be later extended to the treatment of vascular pathologies, such as macular degeneration and certain cardiovascular diseases. Meanwhile, SBD.1 can also be commercialized as reagent for laboratory research on angiogenesis. Taken together, these applications represent a substantial potential market for SBD.1

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 149.45K | Year: 2013

DESCRIPTION (provided by applicant): Psoriasis is a chronic skin disease affecting 2% of the world population. It is characterized by immune infiltrates in lesions and hyperkeratosis, and can be partially remediated with prescription medicines, such as topical retinoids. Despite their great potential, current topical retinoid drugs are typically used at suboptimal doses, due to their side effects. Adverse effects, which include skin irritation, photosensitivity and teratogenicity are common to all 1st and2nd generation retinoids. While the 3rd generation of retinoids appears to have a better teratogenicity safety profile, its skin-adverse effects such as erythema, scaling, dryness, pruritus, and burning are not improved, affecting 10-40% of patients. In an attempt to discover retinoid-like functional compounds with minimal adverse effects, we screened libraries of natural compounds from plants traditionally used for the treatment of skin diseases, with the emphasis on psoriasis. Our research yielded one product candidate (SBD.073) with desired similar gene expression profile to retinol in human skin substitutes (using DNA microarrays) but without any skin irritation, as determined by repeat insult patch test in humans. In further human studies, SBD.073 hasbeen found to be not only non-irritant and non-phototoxic, but, to the contrary, to protect skin from UV-induced erythema. Mechanistic studies showed that, similarly to retinol, SBD.073 induced F9 cell differentiation and normalized structure of the dermal-epidermal junction, but unlike retinol, it did not stimulate the expression of RARG1 - the receptor implicated in skin irritation. Moreover, this retinoid analogue was found to have an excellent anti oxidant and anti-inflammatory activity and no mutagenicity. Here, we propose to validate the proof of principle that SBD.073 is a unique drug-candidate for a greatly improved topical treatment of psoriasis in a comparative study with the existing topical retinoid treatments. We will use a combination of psoriasis-relevant assays, such as TNF-a and IL-17/IL-22 - stimulated organotypic skin substitutes, and animal models (orthokeratosis in mouse tail test, urticuli normalization in rhino mouse and teratogenesis in NMRI mouse) to demonstrate that SBD.073 exceedsthe therapeutic activity of current topical retinoid treatment modalities, while having second- to-none safety and tolerance profile. Taken together, this project should result in the establishment of a proof of principle that SBD.073 is the first skin-protectant retinol analogue fo a greatly improved topical therapy of psoriatic lesions. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Psoriasis is a chronic autoimmune disease affecting millions of people worldwide, in which the immune infiltrates disrupt normal keratinization of the skin. Among the available treatments, retinoids are an important therapeutic option, which is however limited by side effects (retinoid dermatitis, teratogenicity, photosensitivity), which adversely affect the tolerance and patient compliance. Even the more stable, synthetic 3rd generation retinoids, such as adapalene, trigger adverse effects such as erythema, scaling, dryness, pruritus, and burning in 10-40% of patients. Without providing a clear activity gain, better teratogenic profile is their only advantage over the earlier retinoids. Here, we propose to develop a functional analogue of retinoids (named SBD.073), which has been isolated from a traditional medicinal plant used for psoriasis and which has been extensively characterized by our lab in terms of its safety, adverse skin effects as well as skin-normalizing bioactivity, as compared to retinol. From these studies it appears that not only SBD.073 is not a skin irritant, but it protects skin from UV-induced erythema (without being a sunscreen) - an important clinical finding in view of retinoids being used in conjunction with phototherapy. Accordingly, our other clinical case study established SBD.073 to be non-phototoxic. Furthermore, this retinoid analogueis not mutagenic and has better anti-inflammatory properties than retinol, while it retains powerful retinol-like activities - so important in psoriasis treatment - such as the abilit to induce cell differentiation and normalize skin structure by strengthening the dermo- epidermal juncture (basement membrane). Hence, it is reasonable to hypothesize that this compound could be better than any current retinoid treatment for the topical treatment of psoriasis. Here, we propose to test this hypothesis by comparing the activity of SBD.073 to the current topical retinoid therapies in several safety and bioactivity models relevant to psoriasis. This will includ tests on tridimensional skin substitutes stimulated with pro-inflammatory cytokines, 2 mouse models of psoriasis with complementary psoriasis-relevant phenotypes, 1 model of retinoid-induced teratogenicity, as well as phototoxicity and skin irritation tests. If successful, this proect will identify the first bioactive retinoid analogue with skin-protective activity, opening the doorto a new generation of functional retinoids

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