Efficient Syntheses of a Series of Trehalose Dimycolate (TDM)/Trehalose Dicorynomycolate (TDCM) Analogues and Their Interleukin-6 Level Enhancement Activity in Mice Sera

Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
The Journal of Organic Chemistry (Impact Factor: 4.72). 04/2007; 72(5):1627-33. DOI: 10.1021/jo062018j
Source: PubMed


We found an IL-6 level-enhancing compound during our synthetic study of trehalose-6,6'-dimycolate (1, TDM, formerly called cord factor) analogues. TDM is a glycolipid distributed in the cell wall of Mycobacterium tuberculosis and shows significant antitumor activity based on an immunoadjuvant activity. However, due to its significant toxicity, TDM is not yet applicable for practical use. In 1993, Datta and Takayama reported the purification of trehalose-6,6'-dicorynomycolate (2c, TDCM) from Corynebacterium spp. We have previously reported the synthesis of four diastereomeric TDCMs and showed that the synthetic (2R,3R,2'R,3'R)-TDCM (2c, hereafter abbreviated RRRR-TDCM-C14) is identical to natural TDCM; we also demonstrated that 2c and SSSS-TDCM-C14 (3c) showed significant antitumor activity as well as inhibitory activity in experimental lung metastasis based on the immunoadjuvant activity. Furthermore, we found that the significant lethal toxicity in mice by TDM (1) was no longer observed with the shorter-chain analogues of TDCMs. Therefore, we have elucidated that the 2,3-antistereochemistry (RR or SS) of the fatty acid residue is promising for biological activities. The chain length of the fatty acid residue should also be important for the biological activity, and thus, we designed a general synthetic procedure for trehalose diesters with 2,3-antistereochemistry and a series of chain lengths by using Noyori's asymmetric reduction of beta,beta-ketoesters followed by antiselective alkylation according to Frater to give beta,beta-hydroxy alcohols as the key steps. Thus, 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 in mouse serum, and we found that RRRR-TDCM-C14 (2c) and RRSS-TDCM-C14 (4c) showed significant IL-6 level enhancement activities.

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    • "Earlier, we have shown that natural trehalose dimycolate (TDM) or synthetic trehalose dicorynomycolate (STDCM), which is a synthetic derivative of TDM with diminished toxicity, when either were administered 1 h after 10.25 Gy g-radiation, reduced endogenous infection , increased survival, and also enhanced hematopoiesis after 6.5 Gy g photons (Madonna et al. 1989). TDM and STDCM stimulate macrophage activity (Yarkoni et al. 1977, Madonna et al. 1989) and enhance IL-6 in circulation (Nishizawa et al. 2007). STDCM increases endogenous splenic colony formation in mixed-field-irradiated mice (Stewart et al. 1990) and modulates cytokine responses in bone marrow and spleen of mice exposed to sublethal g-radiation (Peterson et al. 1994). "
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    ABSTRACT: A combination therapy for combined injury (CI) using a non-specific immunomodulator, synthetic trehalose dicorynomycolate and monophosphoryl lipid A (STDCM-MPL), was evaluated to augment oral antimicrobial agents, levofloxacin (LVX) and amoxicillin (AMX), to eliminate endogenous sepsis and modulate cytokine production. Female B6D2F1/J mice received 9.75 Gy cobalt-60 gamma-radiation and wound. Bacteria were isolated and identified in three tissues. Incidence of bacteria and cytokines were compared between treatment groups. Results demonstrated that the lethal dose for 50% at 30 days (LD50/30) of B6D2F1/J mice was 9.42 Gy. Antimicrobial therapy increased survival in radiation-injured (RI) mice. Combination therapy increased survival after RI and extended survival time but did not increase survival after CI. Sepsis began five days earlier in CI mice than RI mice with Gram-negative species predominating early and Gram-positive species increasing later. LVX plus AMX eliminated sepsis in CI and RI mice. STDCM-MPL eliminated Gram-positive bacteria in CI and most RI mice but not Gram-negative. Treatments significantly modulated 12 cytokines tested, which pertain to wound healing or elimination of infection. Combination therapy eliminates infection and prolongs survival time but does not assure CI mouse survival, suggesting that additional treatment for proliferative-cell recovery is required.
    Full-text · Article · May 2015 · International Journal of Radiation Biology
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    • "Moreover, when using deuteropyridine as solvent, the 1 H-NMR spectrum of cord factor from TMC 5135 (not shown) (H-1/H19, 5.63 p.p.m.; H-2/H-29, 4.00 p.p.m.; H-3/H-39, 4.46 p.p.m.; H-4/H-49, 3.92 p.p.m.; H-5/H59 and H-6a/H69a, 4.92 p.p.m.; H-6b/H- 69b, 4.46 p.p.m.) did not differ from those reported by Nishizawa et al. (2007) for compounds presenting a 2R,3R/ 29R,39R configuration. On the other hand, the 13 C-NMR spectrum of cord factor from TMC 5135 (Table 2) was similar to those of other cord factors reported in the literature (Nishizawa et al., 2007). Fig. 3. ESI-IT-MS spectrum of mycolic acids from cord factor of M. simiae 'habana' TMC 5135. "
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    ABSTRACT: The structure of cord factor was studied in several strains of Mycobacterium simiae, including 'habana' TMC 5135, considered as highly immunogenic in experimental tuberculosis and leprosy. The mycolic acids liberated from cord factor were identified in all cases as α'-, α- and keto-mycolates. According to the general NMR and MS data, α'-mycolates were mono-unsaturated and contained from 64 to 68 carbon atoms, whereas α-mycolates mainly presented two 2,3-disubstituted cyclopropane rings and a chain length of 80-91 carbon atoms; keto-mycolates mostly contained one cyclopropane ring and 85-91 carbon atoms. Taking into account the (1)H-NMR results, strains varied in the ratio of the different mycolates, and the high levels of keto-mycolates found in the cord factors of TMC 5135 and ATCC 25275(T) stood out. Notably, MS revealed that the odd carbon number series of α-mycolates (C87-C89) predominated in the cord factor of TMC 5135, in contrast to the remaining studied strains, in which the even (C84-C86) and odd carbon number series appeared more equal. The fine structural differences detected among the cord factors studied did not seem to be relevant to the general capacity of these molecules to induce the secretion of tumour necrosis factor alpha, as the cord factors from several strains of M. simiae (TMC 5135, IPK-342 and ATCC 25275(T)) induced similar amounts of this cytokine in RAW 264.7 cells.
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    ABSTRACT: Cationic liposomes are lipid-bilayer vesicles with a positive surface charge that have re-emerged as a promising new adjuvant technology. Although there is some evidence that cationic liposomes themselves can improve the immune response against coadministered vaccine antigens, their main functions are to protect the antigens from clearance in the body and deliver the antigens to professional antigen-presenting cells. In addition, cationic liposomes can be used to introduce immunomodulators to enhance and modulate the immune response in a desirable direction and, thereby, represent an efficient tool when designing tailor-made adjuvants for specific disease targets. In this article we review the recent progress on cationic liposomes as vehicles, enhancing the effect of immunomodulators and the presentation of vaccine antigens.
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