Regulation of phospholipase D activity

1. A method for treating phospholipase D (PLD) initiated polymorphoneutrophil (PMN) inflammation in a subject, comprising

administering to the subject an effective anti-inflammatory amount of a lipoxin analog having the formula

wherein X is R 1 , OR 1 , or SR 1 ;

wherein R 1 is

(i) a hydrogen atom;

(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;

(iii) a cycloalkyl of 3 to 10 carbon atoms;

(iv) an aralkyl of 7 to 12 carbon atoms;

(v) phenyl;

(vi) substituted phenyl

wherein Z i Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R T , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl;

(vii) a detectable label molecule; or

(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;

wherein R T is

(i) a hydrogen atom;

(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;

(iii) a cycloalkyl of 3 to 10 carbon atoms;

(iv) an aralkyl of 7 to 12 carbon atoms;

(v) phenyl;

(vi) substituted phenyl

wherein Z i Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl;

wherein Q 1 is (C═O), SO 2 or (CN), provided when Q 1 is CN, then X is absent;

wherein one of R 2 and R 3 is a hydrogen atom and the other is

(a) H;

(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched;

(c) a cycloalkyl of 3 to 6 carbon atoms, inclusive;

(d) an alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched; or

(e) R a Q 2 R b wherein Q 2 is —O— or —S—; wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b is 0, then R b is a hydrogen atom;

wherein R 4 is

(a) H;

(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;

wherein R 5 is

wherein Z i Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;

wherein Y 1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CH a Z b where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;

wherein R 6 is

(a) H;

(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;

wherein T is O or S, and pharmaceutically acceptable salts thereof, such that PLD initiated polymorphoneutrophil (PMN) inflammation is treated in a subject.

2. The method of claim 1 , wherein said method is performed in vitro.

3. The method of claim 1 , wherein said method is performed in vivo.

4. A method for treating phospholipase D (PLD) initiated superoxide generation or degranulation in a subject, comprising administering to the subject an effective anti-PLD amount of a lipoxin analog having the formula

wherein X is R 1 , OR 1 , or SR 1 ;

wherein R 1 is

(i) a hydrogen atom;

(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;

(iii) a cycloalkyl of 3 to 10 carbon atoms;

(iv) an aralkyl of 7 to 12 carbon atoms;

(v) phenyl;

(vi)substituted phenyl

wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2, —CN, —C(═O)—R T , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl;

(vii) a detectable label molecule; or

(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;

wherein R T is

(i) a hydrogen atom;

(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;

(iii) a cycloalkyl of 3 to 10 carbon atoms;

(iv) an aralkyl of 7 to 12 carbon atoms;

(v) phenyl;

(vi) substituted phenyl

wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2 , —CN, —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl;

(vii) a detectable label molecule; or

(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;

wherein Q 1 is (C═O), SO 2 or (CN), provided when Q 1 is CN, then X is absent;

wherein one of R 2 and R 3 is a hydrogen atom and the other is

(a) H;

(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched;

(c) a cycloalkyl of 3 to 6 carbon atoms, inclusive;

(d) an alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched; or

(e) R a Q 2 R b wherein Q 2 is —O— or —S—; wherein R a is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein R b is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when R b is 0, then R b is a hydrogen atom;

wherein R 4 is

(a) H;

(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;

wherein R 5 is

wherein Z i , Z ii , Z iii , Z iv and Z v are each independently selected from —NO 2, —CN, —C(═O)—R 1 , —SO 3 H, a hydrogen atom, halogen, methyl, —OR x , wherein R x is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;

wherein Y 1 is —OH, methyl, —SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CH a Z b where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;

wherein R 6 is

(a) H;

(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;

wherein T is O or S, and pharmaceutically acceptable salts thereof, such that PLD initiated superoxide generation or granulation is treated in a subject.

5. The method of claim 4 , wherein said method is performed in vitro.

6. The method of claim 4 , wherein said method is performed in vivo.