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trivalent chiral nitrogen compound

By Elaine Tucker,2014-05-28 09:56
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trivalent chiral nitrogen compound

    Research of Trivalent Chiral Nitrogen Compound

    Relationship of Chirality and Activity

    Abstract A Research Plan, By Research of Trivalent Chiral Nitrogen Compound

    Relationship of Chirality and ActivityTo Research and Discuss the Mechanism of

    Biological Macromolecules, and Further Reveals Physiological and Biochemical Mechanisms in vivo. New Model for Drug Evaluation Will Be Established. We Will Provide a New Way For Drug Design and Evaluation.

    keywords Trivalent chiral nitrogen

    Background Chiral substance is prevalence in nature, and many synthetic compounds are chiral. The chiral of compounds is produced by chiral atom, e.g carbon, nitrogen, phosphorus and sulfur. When the atom connect different groups, The atom will exhibit chirality.

    When nitrogen atom connects four groups, It will form quaternary amine compounds, If it connected to four different groups, The nitrogen atom will act as chiral nitrogen characteristics. When nitrogen atom is connected to three different groups, The rest of the lone pair electrons as a group with three other groups constitute a three-dimensional conformation is asymmetric. When the nitrogen atom is in the bridge position, The compound is chiral compound. when nitrogen atom is not in the bridge position, because the molecules are easily turned , the configuration changes easily, therefore, only in very special cases ,we can gain optically active enantiomers.

    Different configuration of chiral nitrogen compounds exhibited different physicochemical properties and biological activity. It is apparently in the quatemary amines. For example, Atracurium, The different enantiomers exhibite different

    pharmacological activity and biochemical properties.

    Research objective: we will prove that activity difference of trivalent chiral nitrogen compounds is relatated with chirality of trivalent chiral nitrogen atom configuration. explain mechanism of trivalent chiral nitrogen atom in biological macromolecular .The eventual we will establish a model for research structure activity relationships of trivalent chiral nitrogen compounds.

    Research ideas: For any trivalent chiral nitrogen atoms, have a common

    characteristic, or that they are connected with the same group, the lone pair of electrons. But due to the different surrounding environment, The lone pair of electrons will present different state, and play different functions.

    As a trivalent chiral nitrogen compounds, The biological activity and biochemical properties of enantiomers may be different. The activity is different when they active in enzymes, receptors and other large molecular biological. or the same role,

    and level is different. In vitro tests, as antagonists or agonists , the effective concentration is different. in vivo tests, pharmacological activity or effective dose is different. For trivalent chiral bridgehead nitrogen atoms compounds(TCBNAC), It can be separated to optically active enantiomers. Sometimes its biological activity is different, and the difference can be validation in vivo or in vitro tests .

    Common trivalent chiral nitrogen compounds(CTCNC,difference from TCBNAC), due to the fourth group is the lone pair of electrons, But there is no bridgehead nitrogen to limit, turn free energy is very low, the whole molecule is in a quickly turn or resonance state. It is difficult to get trivalent nitrogen optically active enantiomer. some special CTCNC can be got, but its half-life is short, and it is more easily racemization in solution , it is very difficult to validate its configuration of activity. and it is difficult to detect the differences in biological activity.

    In fact, For many important macromolecules in organism, Its spatial structure foundation and activity center is closely related with trivalent chiral nitrogen atom. For some very important protein like enzymes or receptors, The trivalent chiral nitrogen atom is very important for its function.

    When some endogenous small molecule activity substances play its role, Trivalent nitrogen chiral atom also plays a key role. For exogenous small molecular compounds such as drugs, Biological activity of them is closely related with trivalent chiral nitrogen atom. It can lead to different activity in different turn state for some activity small molecules. some activity is what we hope, known as the pharmacodynamic activity; some activity is we don't need, may be the foundation of the side effects.

    For most CTCNC with low turn free energy , whether large or small molecular, despite turn or resonance, when they play biological activity, possibly with one kind of specific chiral form, activity of chiral fixed with the activated state of the molecule, activity in the process of implementation may accompanied by turn, may not accompanied by turn, effect site sites corresponding to trivalent chiral nitrogen atom may turn synchronously, may turn with chiral atom chemical bond or configuration changes of the substrate or ligand , in order to complete its biological function.

    It is very important to prove the difference of small molecule trivalent bridgehead nitrogen chiral enantiomers activity , We can study biologically active of macromolecules, and study the activity center or allosteric center that turn free energy of trivalent chiral nitrogen atom is very low .What about the chiral state? as well as trivalent chiral nitrogen atom of the mechanisms and interactions between macromolecules and small molecules, interaction and mechanism between trivalent chiral nitrogen atom and other chiral atom.

    Peptide bond is the important component of polypeptide and protein structure ,

    its essence is the amide bond, generally, the C-N bond and the C = O bond of the peptide bond is in the resonance state, the alpha carbon, the carboxyl carbon, the oxygen of N-terminal amino acid, the nitrogen, the hydrogen linked with nitrogen , the alpha carbon of carboxyl terminal amino acid, six atoms through the two doublebond in resonance state is in an imaginary plane. the nitrogen atom In the peptide bond is trivalent chiral nitrogen atom, which belongs to the low free energy of trivalent chiral nitrogen atom, when hydrogen is involved in intramolecular or intermolecular hydrogen bond formation, turn free energy will become large, similar bridgehead nitrogen status, this is very important for the maintenance of peptide or protein space conception and ensure the biological activity .And sometimes when the ligand or substrate and the active centers or allosteric center jointly exercise the role, the chirality of trivalent chiral nitrogen atom of peptide bond maybe change, and then it maybe play different roles.

    For a large number of CTCNC, it is also important between optically active state and the biological activity, when these compounds(CTCNC) play an active role, the chiral state of the trivalent nitrogen atom may be fixed, a chiral state may play a role in, and its enantiomers may have none of the same role ,might even play opposite activity, that is very important for the efficacy and side effects of drugs.

    The organism macromolecular substances are numerous, there are a lot of activity center or allosteric center, a compound may also have a variety of biological activity and biochemical properties, many models and many sites must be studying for any compounds, so that we can know the biological activity and biochemical properties of the compounds.

    It is very important that researching the relationship between chirality and activity of trivalent chiral nitrogen compounds, and then we can research the importance of trivalent chiral nitrogen compounds for small molecular biological activity and biological chemistry , and we can research the relationship between maccromolecule spatial structure and biological activity or biochemical properties , in order to further explain the normal physiological and biochemical mechanism of action, and then provide basis of drug design and the disease treatment.

    Study plan:

    First of all, we must provide that the chirality of trivalent chiral nitrogen atom is related with biological activity of compound. We can serve the known active compounds as templates, design and synthesis of some detachable racemic compounds of trivalent chiral nitrogen that can not turn. We can confirm its activity by in vitro tests, and then detach enantiomers of trivalent chiral nitrogen compounds, through active contrast test, to obtain relationship information between chirality of chiral nitrogen atoms and the biological activity of compounds .

    synthesis of trivalent chiral nitrogen compounds and validation of biological activity is very important for that .

    Secondly, on the basis of research result above, we must synthesize some new compounds both fluorescence and trivalent bridgehead chiral nitrogen related biological activity, by using them as tools, using single molecule technology and other new technology, research relationship between activity center or allosteric center of biological macromolecules and chirality of trivalent chiral nitrogen atom in biological macromolecules. choice of object and the combination of new techniques is very important.

    The Third, in front of the research results foundation, we can synthesize both fluorescence and CTCNC, to study the chirality of CTCNC that play biological activity.

    The fourth, we can establish some mathematics models that can evaluate the relationship between the chirality of trivalent chiral nitrogen atom and the mechanism of known drugs or other biological substance, analyse of

    pharmacological mechanisms and side effects, provide help for new drug design and clinical treatment .

    Design and synthesis of activity trilavent chiral bridge nitrogen compounds that can be detachable enantiomers

    Active bridgehead trivalent chiral nitrogen compounds, and is attached to the nitrogen atom of the three groups each are not identical, the three group should contain aromatic hydrocarbon, the peptide bond, or a feature structure of the side chain, can also connect a group of pure fat hydrocarbon chain, this plan designed compounds three group respectively (1) benzene derivatives (2) fatty hydrocarbon chain and (3) containing the active effect of substituent on a side chain. They correspond to play a role in the biological macromolecules that can be an enzyme or receptor, these biological macromolecules activity center or the allosteric effect center active with these compounds , exhibit biological activity. These compounds may be receptor antagonists or agonists, may also be an enzyme activator or inhibitor.

    The compounds containing trivalent chiral bridge nitrogen atom , due to its special structure, in addition to this chiral nitrogen, but also there is at least one other chiral atom, the chirality of the other chiral atom related to the chirality of Bridge trivalent chiral nitrogen. If the trivalent chiral bridge nitrogen atoms are connected with three groups of small differences, the difference of compounds may be very small , and if the three groups differ greatly, the influence of other chiral center will increase. design of Compounds should think of the difference between the side chain, and avoid influence of other chiral atom on activity , in order to ensure important for activity of the trivalent chiral nitrogen.See Fig. A:

    R1R2

    Figure A: chirality of two bridgehead carbon is corresponding , instead of one bridge carbon with nitrogen, keeping another bridgehead carbon to be minimal effect.

    To prove the activity difference is contributed by trivalent chiral bridge nitrogen atoms, we can synthesize similar structure compounds that is non bridged ring compound, only nitrogen can turn easily. Through the comparative of activity, that can support the defference contribution of the bridge chiral trivalent nitrogen atoms on activity.

    Following the mother structure of compounds or their derivatives may have biological activity, such as acetylcholine, dopamine, GABA, 5 - serotonin, epinephrine and other benzodiazepines, receptor antagonistic or excited; inhibitors or allosteric effector of enzymes such as proteases, inhibitors of acetylcholinesterase. we should synthesize them for testing.

    N

    O

    HO

    Fig1. derivatives of simple amino acid, their side chains can be various amino acids in the corresponding side chain.

    O

    O

    N

     R

    Fig 2. lactone of derivatives of amino acid, R=side chain of amino acid.

    O

    HO

    NH

    O

    N

     R

    Fig 3. direvatives of ring dipeptides, amino of amino terminal is trivalent chiral

    nitrogen; and in the other hand, the compound is direvatives of GABA.

    N

    O

    O

    HN

    OH

    R

    Fig 4.derivatives of bipeptides, amino of amino terminal is trivalent chiral nitrogen.

    N

    OH

    O

    Fig 5. Derivatives of GABA.

    O

    N

     HOFig 6. Derivatives of GABA.

    O

    OH

     N

    Fig 7. Derivatives of GABA.

    HCO3

    O

    N

    NHSO22

     N

    Fig 8. antagonist of DA acceptor.

    COH3

    SONH22

    HN

    O

     N

    Fig 9. antagonist of DA acceptor.

    S

    Cl

    N Fig 10. Antagonist of DA acceptor

    N

    S

    N Fig 11. Antagonist of DA acceptor

    HN

    O

     N

    Fig 12. Antagonist of 5-HTA acceptor

    O

    NN

    N

Fig 13. Antagonist of 5-HTA acceptor

    O

    N

    OO

    Fig 14. Analogs of acetylcholine

    O

     N

    Fig 15. Analogs of acetylcholine, and then it is derivatives of GABA

    NH2

    N

     O

    Fig 16. derivatives of amide

    ONH2

    NO

    HO

    Fig 17. Dipeptides, the nitrogen atom of C-terminal is trivalent chiral nitrogen

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