18 結核菌細胞表層関連糖脂質TDCM類縁体の系統的不斉合成とIL-6誘導活性(口頭発表の部)

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Interleukin-6 (IL-6) is a multifunctional cytokine exhibiting important roles in host defense, acute phase reaction, immune responses, nerve cell function, and hematopoiesis. Elevated serum IL-6 levels have been observed in a number of pathological conditions including bacterial and viral infections, trauma, autoimmune diseases, inflammations, and malignancies. Now we found that IL-6 level enhancement compound during our synthetic study of trehalose-6,6'-dimycolate (1, TDM, used to be so called cord factor) analogues. TDM is a glycolipid distributed in the cell wall of Mycobacterium tuberculosis, and shows significant anti-tumor activity based on a immunoadjuvant activity. However due to its significant toxicity, TDM was not yet applied for practical use. In 1993, Datta and Takayama reported the purification of trehalose-6,6'-dicorynomycolate (2c, TDCM) from Corynebacterium spp. We have reported the synthesis of four diastereomeric TDCMs based on a strategy of Katsuki-Sharpless epoxidation and then Noyori's BINAP-Ru catalyzed asymmetric reduction of a racemic β-ketolactone. Therefore, we showed that the synthetic (2R,3R,2'R,3'R)-TDCM (2c, hereafter abbreviate to RRRR-TDCM-C_<14>) is identical with natural TDCM, and also demonstrated that 2c and SSSS-TDCM-C_<14> (3c) showed significant anti-tumor activity as well as inhibitory activity of experimental lung metastasis based on the immunoadjuvant activity. Furthermore, we found that the significant lethal toxicity in mice by TDM (1) was no more observed on the shorter analogue TDCMs. Therefore, we have elucidated that the 2,3-anti stereochemistry (RR or SS) on fatty acid residue is promising for biological activities. The chain length of the fatty acid residue should be also important for the biological activity, and thus, we designed general synthetic procedure for trehalose diesters with 2,3-anti stereochemistry and a series of chain length by using Noyori's asymmetric reduction of β-ketoesters and following anti-selective alkylation according to Frater to give β-hydroxy alcohols as the key steps. And we prepared trehalose diesters (TDCM) 2a-d, 3a-d, and 4a-d as well as monoesters (TMCM) 5a-d and 6a-d. Immunological activities of TDCMs and TMCMs were evaluated by determining IL-6 level enhancement on mice serum, and found that RRRR-TDCM-C_<14> (2c) and RRSS-TDCM-C_<14> (4c) show significant IL-6 level enhancement activities.
天然有機化合物討論会の論文
2006-09-15

18 結核菌細胞表層関連糖脂質TDCM類縁体の系統的不斉合成とIL-6誘導活性(口頭発表の部)

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