The immunosuppressive and anti-inflammatory actions of glucocorticoid hormones are mediated by their trans-repression of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) transcription factors. NF-κB is a pivotal mediator of the human immune response regulating the transcription of various proinflammatory and inflammatory mediators. AP-1 is a key mediator of cytokine signalling and required for the activation of numerous proinflammatory genes. Glucocorticoids have long been used to treat chronic inflammatory disease and immunomodulation. However, a wide range of adverse effects also accompanies the beneficial anti-inflammatory and immunomodulating effects of glucocorticoids. Thus, it appears that inhibition of the NF-κB and/or AP-1 transcriptional activation may become an attractive target in the development of novel anti-inflammatory drugs. Terpenoids are a wide-spread group of natural compounds with considerable practical significance. Diverse biological properties have been ascribed to pentacyclic triterpenoid and tetracyclic diterpenoids, such as anti-inflammation, hepato-protection, anticancer, and so on. The utilization of natural products as a source of structural or functional templates for the design and synthesis of a wide variety of novel molecules has been an important aspect of new drug design. Ursonic acid, a pentacyclic triterpenoid, possesses significant cytotoxic activity in many cancer cell lines. On the other hand, isosteviol and steviol are readily prepared from stevioside. Both tetracyclic diterpenoids possess many biological functions such as anti-hypertension, decreasing glucose production, and anti-inflammation. According to the literature, it could be introduced the polar functionalities into unfunctionalized carbocycles or at chemically inactive positions, in order to enhance existing properties or lead to new biological activities. Thus, microbial transformation has been used as an important tool in the structural modification of organic compounds due to its significant regio- and stereoselectivities. Other reports also demonstrated that molecules comprising both amino and alcoholic groups were not only biologically active but also have useful chemical properties. Considering to enhance existing properties or to obtain new potentially bioactive substances, structural modification of ursonic acid, isosteviol, steviol and their derivatives will be achieved either chemically or microbiologically (using microorganism cultures) in the next three years. Due to steroids involving the same sequence of reactions as terpenoids biosynthesis and tetracyclic diterpenoids possessing a formal similarity to steroids, the objective of this study is to obtain immunoinflammatory compounds by targeting activities of inflammation-induced transcription factors of NF-κB and AP-1. The results will provide for further the scientific basis for advances in action mechanism in the future.
|Effective start/end date||8/1/11 → 7/31/12|
- microbial transformation
- biological evaluation