US2015352155A1PendingUtilityA1
Use of anti-aging glycopeptides to enhance pancreatic cell health, survival and improve transplant outcome
Est. expiryJun 4, 2034(~7.8 yrs left)· nominal 20-yr term from priority
A61P 3/10C12N 2501/998C12N 2501/999C12N 2501/90A61K 35/39C12N 5/0676A61P 1/18
33
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Claims
Abstract
The present disclosure relates to an in vitro method for enhancing engraftment of isolated pancreatic cells comprising the step of contacting an isolated pancreatic cell prior to a transplantation in a subject in need thereof, with a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, addition salt with an acid, hydrate or solvate of the compound of general formula I:
Claims
exact text as granted — not AI-modified1 . An in vitro method for enhancing engraftment of isolated pancreatic cells, isolated pancreatic progenitor cells, or both comprising the step of:
a) contacting an isolated pancreatic cell, an isolated pancreatic progenitor cell, or both prior to a transplantation in a subject in need thereof, with a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, addition salt with an acid, hydrate or solvate of the compound of general formula I:
in which:
N is an integer between 1 and 5,
R 4 =H, AA 1 , or AA 1 -AA 2 ,
R 5 =OH, AA 1 , or AA 1 -AA 2 ,
AA 1 and AA 2 independently represent amino acids with a non-polar side chain
and
R 1 , R 2 , R 3 are independent groups in which two of R 1 , R 2 and R 3 are selected from H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 or CH(CH 3 )CH 2 CH 3 and the remaining R 1 , R 2 , R 3 is
in which:
n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′ or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
and
if R 1 =R 2 =H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 3 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 1 =R 3 =H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 2 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 2 =R 3 =H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 1 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′ H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function.
2 . An in vitro method for improving the insulin secretory function of isolated pancreatic beta cells prior to transplantation in a subject in need thereof, comprising the step of:
a) contacting an isolated pancreatic beta cell with a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, addition salt with an acid, hydrate or solvate of the compound of general formula I:
in which:
N is an integer between 1 and 5,
R 4 =H, AA 1 , or AA 1 -AA 2 ,
R 5 =OH, AA 1 , or AA 1 -AA 2 ,
AA 1 and AA 2 independently represent amino acids with a non-polar side chain and
R 1 , R 2 , R 3 are independent groups in which two of R 1 , R 2 and R 3 are selected from H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 or CH(CH 3 )CH 2 CH 3 and the remaining R 1 , R 2 , R 3 is
in which:
n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′ or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
and
if R 1 =R 2 =H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 3 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 1 =R 3 =H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 2 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 2 =R 3 =H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 1 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′ H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function.
3 . An in vitro method for protecting isolated pancreatic cells, isolated pancreatic progenitor cells, or both from immunosuppressant drug toxicity prior to a transplantation in a subject in need thereof comprising the step of:
a) contacting an isolated pancreatic cell, an isolated pancreatic progenitor cell, or both with a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, addition salt with an acid, hydrate or solvate of the compound of general formula I:
in which:
N is an integer between 1 and 5,
R 4 =H, AA 1 , or AA 1 -AA 2 ,
R 5 =OH, AA 1 , or AA 1 -AA 2 ,
AA 1 and AA 2 independently represent amino acids with a non-polar side chain
and
R 1 , R 2 , R 3 are independent groups in which two of R 1 , R 2 and R 3 are selected from H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 or CH(CH 3 )CH 2 CH 3 and the remaining R 1 , R 2 , R 3 is
in which:
n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′ or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
and
if R 1 =R 2 =H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 3 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 1 =R 3 =H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 2 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 2 =R 3 =H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 1 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′ H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function.
4 . An in vitro method for decreasing an inflammatory response of isolated pancreatic cells, isolated pancreatic progenitor cells, or both prior to a transplantation in a subject in need thereof comprising the step of:
a) contacting an isolated pancreatic cell, an isolated pancreatic progenitor cell, or both with a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, addition salt with an acid, hydrate or solvate of the compound of general formula I:
in which:
N is an integer between 1 and 5,
R 4 =H, AA 1 , or AA 1 -AA 2 ,
R 5 =OH, AA 1 , or AA 1 -AA 2 ,
AA 1 and AA 2 independently represent amino acids with a non-polar side chain and
R 1 , R 2 , R 3 are independent groups in which two of R 1 , R 2 and R 3 are selected from H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 or CH(CH 3 )CH 2 CH 3 and the remaining R 1 , R 2 , R 3 is
in which:
n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′ or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
and
if R 1 =R 2 =H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 3 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 1 =R 3 =H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 2 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 2 =R 3 =H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 1 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′ H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function.
5 . A method of transplanting isolated pancreatic cells, isolated pancreatic progenitor cells, or both in a subject in need thereof comprising the steps of:
a) contacting an isolated pancreatic cell, an isolated pancreatic progenitor cell, or both with a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, addition salt with an acid, hydrate or solvate of the compound of general formula I:
in which:
N is an integer between 1 and 5,
R 4 =H, AA 1 , or AA 1 -AA 2 ,
R 5 =OH, AA 1 , or AA 1 -AA 2 ,
AA 1 and AA 2 independently represent amino acids with a non-polar side chain
and
R 1 , R 2 , R 3 are independent groups in which two of R 1 , R 2 and R 3 are selected from H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 or CH(CH 3 )CH 2 CH 3 and the remaining R 1 , R 2 , R 3 is
in which:
n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′ or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
and
if R 1 =R 2 =H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 3 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 1 =R 3 =H, CH 3 , CH 2 Ph, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 2 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 2 =R 3 =H, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , or CH(CH 3 )CH 2 CH 3
then R 1 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′ H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is H, CH 3 , CH 2 OH, CH 2 -glycoside group, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function;
b) transplanting the treated isolated pancreatic cell of step a) in said subject in need thereof.
6 . The method of claim 5 , further comprising step a′) before step a):
a′) isolating pancreatic cells, pancreatic progenitor cells, or both.
7 . The method of claim 5 , further comprising step b′) before step b) contacting the isolated pancreatic cell, the isolated pancreatic progenitor cells, or both of step a) with an immunosuppressant drug.
8 . The method of any one of claim 1 , wherein said isolated pancreatic cell is an isolated alpha cell, an isolated beta cell, an isolated delta cell, an isolated gamma cell, an epsilon cell, or a combination thereof.
9 . The method of claim 1 , wherein said isolated pancreatic cell is an isolated beta cell.
10 . The method of claim 3 , wherein said immunosuppressant drug is one of daclizumab, sirolimus, tacrolimus, cyclosporine, or combinations thereof.
11 . The method of claim 1 , wherein said subject is a human subject.
12 . The method of claim 1 , wherein said isolated pancreatic cell is isolated from a live donor, a cadaveric donor, or combinations thereof.
13 . The method of claim 1 , wherein the compound of formula I is a compound of formula II:
in which: N is an integer between 1 and 5,
and
R 1 , R 2 , R 3 are independent groups in which two of R 1 , R 2 and R 3 are selected from H, CH 3 and the remaining R 1 , R 2 and R 3 is
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″ or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is selected from H, CH 3 , CH 2 OH, CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
and
if R 1 =R 2 =H or CH 3 ,
then R 3 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or
C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is selected from H, CH 3 , CH 2 OH, CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 1 =R 3 =H or CH 3 ,
then R 2 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′=H, OR, N 3 , NR′R″, SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl,
Bn, tosylate, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is selected from H, CH 3 , CH 2 OH, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom H or a free or protected alcohol function,
if R 2 =R 3 =H or CH 3 ,
then R 1 =
in which: n is an integer between 3 and 4,
Y, Y′ are independent groups
in which Y, Y′ H, OR, N 3 , NR′R″, or SR′″,
where R=H, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group, C(═O)-alkyl, or C(═O)—Bn,
R′″=H, alkyl, or acetate group,
R 6 is selected from H, CH 3 , CH 2 OH, or CH 2 —OGP in which GP is a protector group selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 7 =OH, OGP′, NH 2 , N 3 , NHGP′, or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,
R 8 is a hydrogen atom or a free or protected alcohol function.
14 . The method of claim 1 , wherein said compound of formula I is a compound of formula III:
15 . The method of claim 1 , wherein contacting said isolated pancreatic cells is with from about from about 0.01 mg/ml to about 5 mg/ml, or from about 1 mg/ml to about 5 mg/ml of said compound of formula I, formula II or formula Ill.
16 . An isolated pancreatic cell, an isolated pancreatic progenitor cell, or both prepared according to the method of claim 1 .
17 . A method of transplanting isolated pancreatic cells, isolated pancreatic progenitor cells, or both in a subject in need thereof comprising the steps of:
a) transplanting an isolated pancreatic cell, an isolated pancreatic progenitor cell, or both prepared according to the method of claim 1 , in said subject in need thereof.
18 . A method of treating diabetes comprising the step of:
a) transplanting an isolated pancreatic cell, an isolated pancreatic progenitor cell, or both prepared according to the method of claim 1 , in said subject in need thereof.Join the waitlist — get patent alerts
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