SYNTHESIS & APPLICATIONS OF LABELLED FORMYLATING REAGENTS: AMINO ACIDS & PEPTIDE
合成
基本信息
- 批准号:6220428
- 负责人:
- 金额:$ 4.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-08-01 至 2000-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Efficient reagents for formylation have a wide utility in organic
synthesis. In addition to simple and direct formylation of reactive
functional groups, they are used for one carbon extension reactions,
and cyclization of aliphatic and aromatic compounds, through methine
insertion reactions. Several formylating reagents such as
formaldehyde, formic acid, formyl fluoride, formic anhydride or formic
acetic anhydride have been available for non-radioactive synthesis of
a formyl group in organic synthesis for many years. In contrast, only
tritiated formaldehyde at a specific activity of 25-100 mCi/mmole in
1:99 mixture with water is commercially available for
tritioformylation reactions. Several biologically important
compounds, such as folinic acid, an antidote to drugs that act as
folic acid antagonists, Chlorophyll b, an essential compound in
photosynthesis, and a group of bioactive peptides known as chemotactic
peptides (leukocyte chemoattractants which direct the migration of
cells) bear a formyl group necessary for their action. In this last
group, the chemotactic response of the rabbit and human neutrophils to
the synthetic tripeptide N-formyl-methionyl-leucyl-phenylalanine is
well established to be mediated via interaction of the peptide with a
specific receptor. I n addition to stimulating chemotaxis, this
peptide/receptor interaction initiates a number of events in
neutrophils such as lysosomal enzyme release, superoxide formation and
release of calcium. The N-formyl group appears to be essential for
good activity since N-acetylation, removal of the _-amino group, or
replacement by an ethyl group results in loss of biological activity
by a factor of 1,000-10,000. The development of an efficient and high
specific activity tritiated formylation reagent would be extremely
useful for the elucidation of many biological processes. We propose
three possible tritioformylating reagents: p-Nitrophenyl
tritioformate, N-tritioformyloxyphthalimide, and acetic formic
anhydride (AFA). All candidates were synthesized and evaluated during
our exploratory chemistry, but AFA was the most selective and
efficient reagent. The deuterated form of AFA was synthesized in
three steps: 1. Synthesis of superdeuteride from LiD; 2. Reduction
of CO2 to lithium formate (DCOOLi) by superdeuteride; and 3. Reaction
of acetyl chloride with DCOOLi to form acetic formic anhydride
(CH3COOCOD) The deuteriated AFA was used for formylation of
L-phenylalanine and L-methionine. 3H AFA formed from supertritide at
20% tritium abundance was used for N-tritioformylation of
methionyl-leucylphenylalanine (MLP) and the formylated peptide was
isolated in high yield at 100% radiochemical purity. The analogous
synthesis using supertritide at 100% tritium content yielded the
radiochemically pure N-tritioformyl-MLP at 95% chemical yield. To our
knowledge, this is the first demonstration of N-formylation at 100%
tritium incorporation. The following general procedure describes the
synthesis of the reagent at the maximum specific activity and its
highly efficient application in the N-tritioformylation of a
tripeptide. Supertritide (0.2 mmole) at the theoretical specific
activity was prepared prior to the synthesis of tritiated lithium
formate. Carbon dioxide (8 mL) was injected in the reaction vessel
and reduced for 1 hour to furnish high specific activity T-COOLi.
Acetyl chloride (0.18 mmole, 7 _L) in dry ether (100 _L) was then
injected into the reaction vessel and the suspension was stirred at
room temperature for two hours to form acetic [3H]formic anhydride.
The reagent in ether solution was vapor transferred to a second
reaction vessel. A solution of methionylleucylphenylalanine (MLP, 10
mg, 0.0025 mmole) in glacial acetic acid (l mL) was injected, and the
reaction was stirred for 1 hour at room temperature to form
N-[3H]-formylmethionyl-leucylphenylalanine (F-MLP). At the end of the
reaction, excess reagent was destroyed by the addition of methanol
(0.5 mL), and the solvents were removed under vacuum. The dried
residue was dissolved in methanol (1 mL) for analysis. Radio-HPLC
analysis gave a specific activity of 28.6 Ci/mmole, and 95% chemical
yield. Extensive 1H/3H NMR analysis showed the desired product with
the formyl tritium at _ 8.1 ppm in the tritium spectrum and close to
100% radiochemical purity.
甲酰化的高效试剂在有机化学中有着广泛的应用
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MANOUCHEHR SALJOUGHIAN其他文献
MANOUCHEHR SALJOUGHIAN的其他文献
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{{ truncateString('MANOUCHEHR SALJOUGHIAN', 18)}}的其他基金
REDUCTIVE CLEAVAGE OF ALIPHATIC NITRO GROUPS W/ TRIBUTYLTIN TRITIDE: TRITIUM NMR
使用三丁基锡对脂肪族硝基进行还原裂解:氚 NMR
- 批准号:
6500498 - 财政年份:2000
- 资助金额:
$ 4.24万 - 项目类别:
RADICAL INDUCED DEAMINATION OF PRIMARY & SECONDARY AMINES BY TRIBUTYLTIN TRITIDE
自由基引发的初级脱氨
- 批准号:
6500500 - 财政年份:2000
- 资助金额:
$ 4.24万 - 项目类别:
TRITIUM LABELLING OF DNA & RNA BY CHEMICAL & ENZYMATIC SYNTHESIS
DNA 氚标记
- 批准号:
6500521 - 财政年份:2000
- 资助金额:
$ 4.24万 - 项目类别:
SYNTHESIS OF VERY HIGH SPECIFIC ACTIVITY N TRITIOACETOXYPHTHALIMIDE: TRITIUM NMR
极高比活度 N 三硫乙酰氧基邻苯二甲酰亚胺的合成:氚 NMR
- 批准号:
6500499 - 财政年份:2000
- 资助金额:
$ 4.24万 - 项目类别:
TRITIUM LABELLING OF GEMFIBROZIL: ANTIBIOTICS & KILLING INTRACELLULAR BACTERIA
Gemfibrozil 的氚标记:抗生素
- 批准号:
6500522 - 财政年份:2000
- 资助金额:
$ 4.24万 - 项目类别:
SYNTHESIS & APPLICATIONS OF LABELLED FORMYLATING REAGENTS: AMINO ACIDS & PEPTIDE
合成
- 批准号:
6500501 - 财政年份:2000
- 资助金额:
$ 4.24万 - 项目类别:
NEW TRITIUM LABELLING REAGENTS & TECHNIQUES SYNTHESIS REVIEW ARTICLE
新型氚标记试剂
- 批准号:
6500532 - 财政年份:2000
- 资助金额:
$ 4.24万 - 项目类别:
NEW TRITIUM LABELLING REAGENTS & TECHNIQUES: SYNTHESIS REVIEW ARTICLE
新型氚标记试剂
- 批准号:
6119744 - 财政年份:1998
- 资助金额:
$ 4.24万 - 项目类别:
TRITIUM LABELLING OF GEMFIBROZIL: ANTIBIOTICS & KILLING INTRACELLULAR BACTERIA
Gemfibrozil 的氚标记:抗生素
- 批准号:
6220449 - 财政年份:1998
- 资助金额:
$ 4.24万 - 项目类别:
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