**5. Further investigation of human sebaceous fatty acids combined with chemical synthesis: Structure-activity relationship of oxa-fatty acids**

C16:1Δ6 has a double bond and, consequently, its stability is a concern, which raises doubts regarding adequate stability of C16:1Δ6 in products. The stability of C16:1Δ6 can be improved by replacing the unsaturated fatty acids with the corresponding oxa-fatty acids (Alkoxy fatty acids). Such a change would also be expected to lead to an improvement in antimicrobial properties of the fatty acid. We describe the results of our investigations regarding such a replacement in the section below.

Improvement of Atopic Dermatitis by Human Sebaceous Fatty Acids and Related Lipids 321

We found that *cis*-6-hexadecenoic acid (C16:1Δ6) displayed a selective antimicrobial activity that was unique among human sebaceous lipids. It was suggested that topical application of C16:1Δ6 to the skin of AD patients, who have lower levels of C16:1Δ6 in skin lipids than healthy controls, was effective for treatment of this skin condition. We proposed an industrial process for the production of C16:1Δ6 using *Rhodococcus* sp. An oxygencontaining analog of C16:1Δ6 (7-oxaheptadecanoic acid) was found to be more effective against microorganisms such as *S.aureus* and *Malassezia* sp. that are associated with skin disorders. It was proposed that the best oxa-fatty acid derivative of C16:1Δ6 could be

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**6. Conclusion** 

**7. References** 

#### **5.1 Review of the antimicrobial activities of oxa-fatty acids**

Although oxa-fatty acids are widely used as intermediate chemicals in fine chemical fields such as medicine, agriculture and fragrance, there have only been a few reports of the antimicrobial activity of oxa-fatty acids. N-alkoxyacetic acid and its methyl ester showed good antifungal activity against *Aspergillus niger*, *Myrothecium verrucaria*, and *Trichoderma viride* (Gershon et al., 1979). In addition, 4-oxatetradecanoic acid, which is an inducer of myristic acid β-oxidation, displayed antifungal activity against *Cryptococcus neoformans* and also antiviral activity against human immunodeficiency virus I (Langner et al., 1992). These studies indicate that oxa-fatty acids of C16:1Δ6, in which the double bond has been replaced with an ether bond (7-oxaheptadecanoic acid or 6-decyloxy hexanoic acid), will maintain their antibacterial activity and will also have a novel function, that is antifungal activity.

#### **5.2 Synthesis and evaluation of a C16 oxa-fatty acid**

An oxygen-containing analog of C16:1Δ6 (oxa-fatty acid:7-oxaheptadecanoic acid) was synthesized by condensation of *n*-decanol with 6-bromo-hexanoic acid under alkaline conditions. The antimicrobial activities of purified 7-oxaheptadecanoic acid were then compared with those of C16:1Δ6. The oxa-fatty acid analog of C16:1Δ6, 7 oxaheptadecanoic acid, retained the selective antimicrobial activity of C16:1Δ6, being effective against *S. aureus* but not against *S. epidermidis* (Fig. 11), and, displayed similar activity to C16:1Δ6 against *Propinibacterium acnes*, which is associated with AD (Ishibashi et al., 2009). In addition, 7-oxaheptadecanoic acid had gained an additional anti-yeast activity against *Malassezia*, which is associated with skin disorders such as seborrhea dermatitis and AD (Tajima et al., 2008). Moreover, the best molecule for treatment of skin disorders such as seborrhea dermatitis and AD could be selected by means of structureactivity relationships (Sugai et al., in preparation).

Fig. 11. Antibacterial activity of 7-oxaheptadecanoic acid. A: *S. aureus*; B: *S. epidermidis* 
