Nylon-3 co-polymers and synthetic lung surfactant compositions containing same
Non-natural oligomers have recently shown promise as functional analogues of lung surfactant proteins Band C (SP-B and SP-C), two helical and amphiphilic proteins that are clitical for normal respiration. The generation of non-natural mimics of SP-B and SP-C has previously been restlicted to step-by-step, sequence-specific synthesis, which results in discrete oligomers that are intended to manifest specific structural attributes. Presented herein an alternative approach to SP-R mimicry that is based on sequence-random copolymers containing cationic and lipophilic subunits. These materials, members of the nylon-3 family, arc prepared by ling-opening polymelization of 13-lactams. The best of the nylon-3 polymers display promising in vitro surfactant activities in a mixed lipid film. Pulsating bubble surfactometry data indicate that films containing the most surface-active polymers attain adsorptive and dynamic-cycling properties that surpass those of discrete peptides intended to mimic SP-B.
1. A method of treating infant, acute, or adult respiratory distress syndromes, and pulmonary disorders involving deficient or dysfunctional lung surfactant in mammals, the method comprising:
administering to a mammalian subject in need thereof an artificial lung surfactant composition comprising a nylon-3 homopolymer or nylon-3 copolymer as an artificial lung surfactant present in the artificial lung surfactant composition in an amount effective to treat a respiratory distress syndrome or pulmonary disorder involving deficient or dysfunctional lung surfactant in the mammalian subject, wherein monomers of the nylon-3 homopolymer or nylon-3 copolymer are selected from the group consisting of:
wherein:
R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl; or
one of R 3 and R 4 combined with one of R 5 and R 6 , together with the carbon atoms to which they are attached, define a cyclic moiety “A”
wherein “A” is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic;
provided that at least two of R 3 , R 4 , R 5 , or R 6 are not hydrogen; and
wherein “n” is a positive integer.
2. The method of claim 1 , wherein the nylon-3 homopolymer or nylon-3 copolymer is a nylon-3 random copolymer.
3. The method of claim 1 , wherein the nylon-3 homopolymer or nylon-3 copolymer is a nylon-3 non-random copolymer.
4. The method of claim 1 , wherein the nylon-3 homopolymer or nylon-3 copolymer is a nylon-3 block copolymer.
5. The method of claim 1 , which is a method treating infant, acute, or adult respiratory distress syndromes.
6. The method of claim 1 , wherein:
one of R 3 and R 4 combined with one of R 5 and R 6 , together with the carbon atoms to which they are attached, define a cyclic moiety “A”
wherein “A” is selected from the group consisting of substituted or unsubstituted C 5 -C 12 cycloalkyl, C 5 -C 12 cycloalkenyl, and five- to twelve-membered heterocyclic; and
the other of R 3 and R 4 and the other of R 5 and R 6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alklyaryl, amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.
7. The method of claim 6 , wherein “A” is substituted or unsubstituted C 5 -C 12 cycloalkyl.
8. The method of claim 6 , wherein “A” is substituted or unsubstituted C 5 -C 12 cycloalkenyl.
9. The method of claim 6 , wherein “A” is substituted or unsubstituted five- to twelve-membered heterocyclic.
10. The method of claim 6 , wherein the other of R 3 and R 4 and the other of R 5 and R 6 are independently selected from the group consisting of substituted or unsubstituted C 1 -C 6 -alkyl, aryl, and C 1 -C 6 -alklyaryl.
11. The method of claim 6 , wherein the other of R 3 and R 4 and the other of R 5 and R 6 are independently selected from the group consisting of substituted or unsubstituted amino, protected-amino, amino-C 1 -C 6 -alkyl, and protected-amino-C 1 -C 6 -alkyl.
12. The method of claim 6 , wherein the nylon-3 homopolymer or the nylon-3 copolymer is a nylon-3 random copolymer.
13. The method of claim 6 , wherein the nylon-3 homopolymer or the nylon-3 copolymer is a nylon-3 non-random copolymer.
14. The method of claim 6 , wherein the nylon-3 homopolymer or the nylon-3 copolymer is a nylon-3 block copolymer.
15. The method of claim 6 , which is a method treating infant, acute, or adult respiratory distress syndromes.