Synthesis, conformational analysis and bioactivity of Lan-7, a lanthionine analog of TT-232

Li, Haitao; Jiang, Xiaohui; Howell, Stephen B.; Goodman, Murray

doi:10.1002/(sici)1099-1387(200001)6:1<26::aid-psc231>3.0.co;2-6

Cited by 21 publications

(18 citation statements)

References 12 publications

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“…22,41,42 The fact that peptide 3b is much more potent than L-363,301 in the cellular assay might point to a biological mode of action that is not dominated by the somatostatin receptors such as that assumed in the case of TT-232. 26,43 Another indication for this finding is that the Lys residue, which is present in all active somatostatin analogues, can be replaced by Nle without loss of activity in the cellular assay.…”

Section: Resultsmentioning

confidence: 98%

“…24,25 Another proof is that the binding affinities of TT-232 to all cloned somatostatin receptors are very low compared to that of somatostatin. 26 Our objective was to develop somatostatin or L-363,301 analogues which are further reduced in ring size and bear mostly hydrophobic, nonnatural residues which in general are used for better pharmacological efficacy and ADME profiles. Herein, we report the results of our efforts, which led to cyclic pentapeptides with high antiproliferative activity in a cellular assay with A431 human epidermoid carcinoma cells.…”

Section: Introductionmentioning

confidence: 99%

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Structure−Activity Relationship Studies Optimizing the Antiproliferative Activity of Novel Cyclic Somatostatin Analogues Containing a Restrained Cyclic β-Amino Acid

et al. 2005

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The cyclic somatostatin analogue cyclo[Pro(1)-Phe(2)-D-Trp(3)-Lys(4)-Thr(5)-Phe(6)] (L-363,301) displays high biological activity in inhibiting the release of growth hormone, insulin, and glucagon. According to the sequence of L-363,301, we synthesized a number of cyclic hexa- and pentapeptides containing nonnatural alpha- and beta-amino acids. The N- fluorenylmethoxycarbonyl protected cyclic beta-amino acid [1S, 2S, 5R]-2-amino-3,5-dimethyl-2-cyclohex-3-enecarboxylic acid (cbetaAA), for the replacement of the Phe(6)-Pro(1) moiety of L-363,301, was synthesized in two steps by an enantioselective multicomponent reaction using (-)-8-phenylmenthol as a chiral auxiliary. The resulting peptide cyclo[cbetaAA(1)-Tyr(2)-D-Trp(3)-Nle(4)-Thr(Trt)(5)] (Trt = triphenylmethyl) shows high antiproliferative effects in an in vitro assay with A431 cancer cells. The same peptide without the Trt group does not reveal any biological activity, whereas L-363,301 and closely related hexapeptides show only minor activity. By comparison of the solution structure of cyclo[cbetaAA(1)-Tyr(2)-D-Trp(3)-Nle(4)-Thr(Trt)(5)] with the structure of l-363,301, a nearly perfect match of the betaII'-turn region with d-Trp in the i + 1 position was observed. The cyclic beta-amino acid cbetaAA is likely needed for the bioactive conformation of the peptide.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Structure−Activity Relationship Studies Optimizing the Antiproliferative Activity of Novel Cyclic Somatostatin Analogues Containing a Restrained Cyclic β-Amino Acid

et al. 2005

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“…In another synthesis, DEPBT was used for the cyclization of the lanthionine analog of TT‐232 (Scheme ) 21. Lanthionines are monosulfide analogs of cystine and constituents of peptide lantibiotics, which provides more constrained peptide structures with greater stability toward enzymatic degradation compared to the labile disulfide bridge of cysteine in natural or unnatural cyclic peptide sequences.…”

Section: Resultsmentioning

confidence: 99%

An adaptive MR‐compatible lens and objective

Maclaren

Schneider

Herbst

et al. 2011

Concepts Magn Reson

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This work presents an MR-compatible adaptive liquid lens, designed to form part of an in-bore optical imaging system. The lens is integrated into a wide-angle objective, which is suitable for use with a camera mounted above the head coil to monitor subject head motion. Compatibility tests indicate that focusing of the lens is unaffected by the static, gradient, or radio frequency (RF) fields of the scanner. Field mapping shows that no B 0 field distortions are visible with the system mounted 55 mm above a water-filled phantom. The total increase in RF noise observed on a 1.5-T system when using the lens and lighting setup is less than 2%, and this is mostly attributable to the lighting. This work was originally motivated by head tracking for prospective motion correction; however, the lens may have other applications whenever high-quality optical images are required in the MR environment and motion of the object makes a fixed lens unsuitable.

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“…Advances in biotechnology have provided a wide range of therapeutically active and commercially available biologic large molecules as protein and peptide drugs [1][2][3]. However, oral administration of these drugs has been highly limited due to the stability and the difficulties to cross the gastrointestinal membrane.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery

Li¹,

Song²,

Oie³

et al. 2017

Med chem (Los Angeles)

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The progress in oral absorption of protein and peptide drugs has been hampered by the difficulty in transporting larger molecules across the gastrointestinal membrane. We are reporting here a study of the design and synthesis of cholic acid-peptide conjugates for peptide drug delivery through gastrointestinal track mediated by bile acid transporter. As principal samples, three small cholic acid-peptide conjugates containing a biodegradable ester bond via threonine linker have been synthesized. In order to introduce ester bond between cholic acid and peptides, conventional solid phase synthesis is not practicable, thus solution phase was employed. The threonine moiety was chosen to introduce a hydroxyl group, on which an ester bond can be formed with different peptides. The threonine moiety also provides the necessary negative charge adjacent to the C24 position as required for transport recognizing by the bile acid transporter in the ilue epicell. The synthetic process was based on DCC chemistry. By using catalytic amounts of N-hydroxysuccinimide the procedure for amide coupling was simplified and shortened while maintaining high efficiency. Esterification using ethyl acetate in the presence of triethylamine selectively introduced an ester bond at the C27 position giving higher yield with no protection on other three hydroxyls. The work also demonstrated that in solution phase synthesis of these peptide conjugates fluoride ion (F -) was more efficient than piperidine to cleave Fmoc from the amino group.Cell culture experiment showed the efficiencies of transporting of the conjugates and the dissociation of the conjugates detected by HPLC, suggesting that the cholic acid conjugates linked by degradable ester bond can be used as bigger molecule drugs delivering template. Further study would be designed by using more different linkers that would be also biodegradable bonds, such as thioester and so forth.

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Synthesis, conformational analysis and bioactivity of Lan-7, a lanthionine analog of TT-232

Cited by 21 publications

References 12 publications

Structure−Activity Relationship Studies Optimizing the Antiproliferative Activity of Novel Cyclic Somatostatin Analogues Containing a Restrained Cyclic β-Amino Acid

Structure−Activity Relationship Studies Optimizing the Antiproliferative Activity of Novel Cyclic Somatostatin Analogues Containing a Restrained Cyclic β-Amino Acid

An adaptive MR‐compatible lens and objective

Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery

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