2f3f: Difference between revisions

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==Overview==

Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide, inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were, designed and synthesized. Analogues containing dithia, dioxa, oxathia, and, carbathia macrocycles were synthesized by methods relying on ring-closing, olefin metathesis for the dioxa analogues and by alkylation of thiolates, or bisthiolates for the others. Molecular modeling suggested that the, incorporation of piperidine units appended to the macrocycles improved, interactions through additional H-bonds and introduced further rigidity., These were synthesized in enantiomerically pure form using, enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory, activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was, observed with several macroheterocyclic inhibitors and structure-activity, relationship (SAR) correlations were deduced. Cocrystal structures of two, synthetic analogues revealed interesting and unexpected binding, interactions.

Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa analogues and by alkylation of thiolates or bisthiolates for the others. Molecular modeling suggested that the incorporation of piperidine units appended to the macrocycles improved interactions through additional H-bonds and introduced further rigidity. These were synthesized in enantiomerically pure form using enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was observed with several macroheterocyclic inhibitors and structure-activity relationship (SAR) correlations were deduced. Cocrystal structures of two synthetic analogues revealed interesting and unexpected binding interactions.

==About this Structure==

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[[Category: Memapsin 2]]

[[Category: Single protein]]

[[Category: Rondeau, J.M.]]

[[Category: Rondeau, J M.]]

[[Category: AXF]]

[[Category: alzheimer's disease]]

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[[Category: memapsin2]]

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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:17:17 2008''

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@@ Line 4: / Line 4: @@
 ==Overview==
-Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide, inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were, designed and synthesized. Analogues containing dithia, dioxa, oxathia, and, carbathia macrocycles were synthesized by methods relying on ring-closing, olefin metathesis for the dioxa analogues and by alkylation of thiolates, or bisthiolates for the others. Molecular modeling suggested that the, incorporation of piperidine units appended to the macrocycles improved, interactions through additional H-bonds and introduced further rigidity., These were synthesized in enantiomerically pure form using, enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory, activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was, observed with several macroheterocyclic inhibitors and structure-activity, relationship (SAR) correlations were deduced. Cocrystal structures of two, synthetic analogues revealed interesting and unexpected binding, interactions.
+Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa analogues and by alkylation of thiolates or bisthiolates for the others. Molecular modeling suggested that the incorporation of piperidine units appended to the macrocycles improved interactions through additional H-bonds and introduced further rigidity. These were synthesized in enantiomerically pure form using enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was observed with several macroheterocyclic inhibitors and structure-activity relationship (SAR) correlations were deduced. Cocrystal structures of two synthetic analogues revealed interesting and unexpected binding interactions.
 ==About this Structure==
@@ Line 14: / Line 14: @@
 [[Category: Memapsin 2]]
 [[Category: Single protein]]
-[[Category: Rondeau, J.M.]]
+[[Category: Rondeau, J M.]]
 [[Category: AXF]]
 [[Category: alzheimer's disease]]
@@ Line 22: / Line 22: @@
 [[Category: memapsin2]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 17:24:45 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:17:17 2008''