Our data demonstrated that CAM at a clinically achievable dose prevented cigarette smoke-induced emphysema by modulating lung inflammation. This study supports the possibility that low-dose CAM treatment might provide a new therapeutic strategy for chronic obstructive pulmonary diseases.

Introduction of an acyl group to the 3-O-position of erythromycin A derivatives instead of L-cladinose led to a novel class of macrolide antibiotics that we named "acylides". The 3-O-nitrophenylacetyl derivative TEA0777 showed significantly potent activity against not only erythromycin-susceptible Gram-positive pathogens but also inducibly macrolides-lincosamides-streptogramin B (MLS(B))-resistant Staphylococcus aureus and efflux-resistant Streptococcus pneumoniae. These results indicated that acylides have potential as next-generation macrolide antibiotics.

Although erythromycin A contains five hydroxyl groups, regioselective methylation at the C-6 hydroxyl group was achieved to the extent of 90%when a 9-0-substituted erythromycin A 9-oxime was employedas substrate.The methylation and its selectivity are dependent on an O-protecting group at the 9-oxime, solvent, base, and methylating reagent. In particular, the use ofa polar aprotic solvent is indispensable for the methylation.Among the 9-oxime derivatives, Erythromycin A (1) is one of the most important macrolide antibiotics for treating respiratory, cutaneous, and genital infections.2'3* It is extremely unstable to acid and undergoes dehydration in vivo to an inactive 6,9 : 9, 12-spiroketal, anhydroerythromycin A (2), when administered orally.Clarithromycin (6-0-methylerythromycin A) (3) also has strong antibacterial activity but is more stable to acid than 1 due to the presence of the C-6 methoxy group.4' 5) Accordingly, 3 exhibits higher concentrations in the lung and plasma than 1, when administered orally to animals.6) Since 1 has five hydroxyl groups, it is difficult to alkylate the C-6 hydroxyl group selectively. In the preceding paper,7) we reported the synthesis of 3 via 2'-0,3'-7V-bis(benzyloxycarbonyl)-JV-demethylerythromycin A (4). In spite of manyattempts to methylate 4 under a variety of reaction conditions, methylation occurs at the secondary C-ll hydroxyl rather than the tertiary C-6 hydroxyl group. Under optimum conditions the desired 6-O-methyl derivative (5) was obtained in 39% yield (94% pure by HPLC analysis), which was contaminated with the 6,ll-di-O-methyl and 6,12-di-O-methyl derivatives (6 and 7). The ll-0-methylated compound (8) was formed in 42% yield. If the ll position was protected as the O-methoxyethoxymethyl, O-trimethylsily^or the 1 1 , 12-cyclic carbonate derivative,8) the corresponding 9-0-methyl derivatives were obtained exclusively as the 6,9-hemiacetals.2'-O,3'-A^-Bis(benzyloxycarbonyl)-7V-demethylerythromycin B (9), which lacks the hydroxyl group in the 12 position can be methylated to give the 6-O-methyl derivative in 87% yield.9) This suggested that the conformation of the aglycone ring of erythromycin derivatives may influence the selectivity of methylation. Wetherefore investigate other derivatives with conformation of the aglycone ring different than that of 1. Wehave found that 9-oxime derivatives of 4, namely 2'-0,3'-N-bis(benzyloxycarbonyl)-iVdemethylerythromycin A 9-oxime (10) and its O-substituted oxime derivatives react with methyl iodideOur unpublished results.

A novel series of acylides, 3-O-(aryl)acetylerythromycin A derivatives, were synthesized and evaluated. These compounds have significant potent antibacterial activity against not only Gram-positive pathogens, including inducibly macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens, such as H. influenzae. 6,9:11,12-dicarbonate acylide 47 (FMA0122) was twice as active against H. influenzae than azithromycin, whereas it showed only moderate in vivo efficacy in mouse protection tests. However, the 11,12-carbamate acylide 19 (TEA0929), which showed potent antibacterial activity against almost all of the main causative pathogens of community-acquired pneumonia tested, exhibited excellent in vivo efficacy comparable to those of second-generation macrolides.