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1.
Org Lett ; 8(16): 3429-31, 2006 Aug 03.
Article in English | MEDLINE | ID: mdl-16869627

ABSTRACT

[reaction: see text] We have found that beta-ketophosphonic acids can undergo facile dephosphonylation under fairly mild conditions. The rate of dephosphonylation is dependent on the electronic nature of the substituent on the carbon atom alpha to phosphorus, with electron-withdrawing groups accelerating the process. 31P NMR studies were used to probe the mechanism for the process.

2.
Bioorg Med Chem ; 13(21): 5936-48, 2005 Nov 01.
Article in English | MEDLINE | ID: mdl-16140539

ABSTRACT

The enediyne moiety is a versatile functional group found in natural anticancer and anti-infective agents, undergoing the Bergman cyclization reaction to afford a diradical which cleaves double-stranded DNA. We have incorporated the enediyne group into 10- (4-10) and 12-membered ring (11) cyclic amino acids and dipeptides, respectively, and explored their relative reactivity toward cyclization, varying N-substitution in the case of the 10-membered ring substrate, which gave the expected cyclization products in good yields when using either thermal conditions in the presence or absence of microwave irradiation. The N-tosyl substituted derivative (4) was shown to nick double-stranded supercoiled DNA. N-Arylsulfonyl substitution on the ring promoted the cyclization, when compared to N-mesyl or acyl substitution, possibly because of a pi-pi stacking effect as an endo-relationship of the aryl group with the enediyne was demonstrated in both the solid state and in solution. The 12-membered ring enediyne dipeptide (11) was inert to the Bergman cyclization under a variety of conditions. When this substrate was irradiated with ultraviolet light, regio- and stereospecific reduction was observed in which one of the alkynes was reduced to a Z-olefin (47).


Subject(s)
Amino Acids, Cyclic/chemistry , Amino Acids, Cyclic/pharmacology , Amino Acids/chemistry , Amino Acids/chemical synthesis , Benzene/chemistry , Amino Acids/pharmacology , Animals , Cattle , Crystallography, X-Ray , Cyclization , DNA Damage/drug effects , Enediynes , Molecular Structure , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/drug effects
3.
J Am Chem Soc ; 127(10): 3473-85, 2005 Mar 16.
Article in English | MEDLINE | ID: mdl-15755167

ABSTRACT

We investigated the formation of macrocycles from alpha,omega-diynes in cobalt-mediated co-cyclotrimerization reactions. Long-chain alpha,omega-diynes underwent metal-mediated [2 + 2 + 2] cycloadditions with nitriles, cyanamides, or isocyanates in the presence of CpCo(CO)2 (Cp = cyclopentadienide) to yield pyridine-containing macrocycles, i.e., meta- and para-pyridinophanes, such as 5m/5p, 35m/35p, and 41m/41p. The regioselectivity of these reactions was affected by the length and type of linker unit between the alkyne groups, as well as by certain stereoelectronic factors. An analogous alpha,omega-cyano-alkyne, 28, combined with an alkyne to yield two isomeric meta-pyridinophanes, such as 5m and 29m, and an ortho cycloadduct (benzannulation product), such as 29o. We developed a reaction protocol for these cobalt-based [2 + 2 + 2] cycloadditions that involves markedly improved conditions such that this process offers a convenient, flexible synthetic approach to macrocyclic pyridine-containing compounds. For example, diyne 6 reacted with p-tolunitrile in 1,4-dioxane to give 7p and 7m (7:1 ratio) in 87% yield at a moderate temperature of ca. 100 degrees C in 24 h without photoirradiation or syringe-pump addition. Isocyanates were also effective reactants, as exemplified by the formation of 44p almost exclusively (44p:44m > 50:1) in 64% yield from diyne 8 and 2-phenylethylisocyanate. By using this improved protocol we were able to co-cyclotrimerize long-chain alpha,omega-diynes with alkynes in certain cases to demonstrate a successful macrocyclic variant of the Vollhardt reaction. For instance, diyne 6 reacted with dipropylacetylene to give paracyclophane 57p and benzannulene 57o (2:1 ratio) in 29% yield.

4.
Org Lett ; 5(24): 4537-40, 2003 Nov 27.
Article in English | MEDLINE | ID: mdl-14627377

ABSTRACT

[reaction: see text] Cobalt-mediated [2 + 2 + 2] cycloaddition of alpha,omega-diynes and isocyanates provides a direct approach to macrocyclic 2-oxopyridinophanes. This macrocyclization process, which proceeded most efficiently with aliphatic isocyanates, was conveniently performed at a moderate temperature (85 degrees C) without irradiation or syringe-pump addition.

5.
J Med Chem ; 45(24): 5303-10, 2002 Nov 21.
Article in English | MEDLINE | ID: mdl-12431057

ABSTRACT

Butabindide, 1, was previously reported as a potent inhibitor (IC50 = 7 nM) of the serine protease enzyme tripeptidyl peptidase II (TPPII), an endogenous protease that degrades cholecystokinin-8 (CCK-8). We found that 1 has some inherent chemical instability, yielding diketopiperazine 2 fairly readily under mimicked physiological conditions. We therefore prepared imidazoles 3, which are void of 1's inherent instability, and have found that our novel analogues maintained comparable TPPII inhibitory activity (e.g.,for 3c, IC50 = 4 nM) as 1.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Indoles/chemical synthesis , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/chemical synthesis , Aminopeptidases , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases , Enzyme Inhibitors/chemistry , Imidazoles/chemistry , Indoles/chemistry , Models, Molecular , Serine Proteinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship
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