Selective coupling of methotrexate to peptide hormone carriers through a gamma-carboxamide linkage of its glutamic acid moiety: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate activation in salt coupling.

Nagy, Attila; Szőke, Balázs

doi:10.1073/pnas.90.13.6373

Cited by 28 publications

(24 citation statements)

References 17 publications

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“…It turned out that even bulky molecules could be linked to the -amino group of the D-Lys 6 moiety without significant loss of the high binding affinity of the peptide portion to receptors for LHRH. This bulk tolerance was exploited in our attempts to create cytotoxic LHRH hybrids in which diverse cytotoxic radicals were attached covalently to the D-Lys side-chain of the LHRH carrier agonists or antagonists (21,47). The cytotoxic compounds included alkylating agent melphalan, DNA strandbreaker cross-linking agent cisplatin, antimetabolite methotrexate and anthracycline derivative 2-(hydroxymethyl)anthraquinone.…”

Section: Design and Synthesis Of Targeted Cytotoxic Analogs Of Lhrhmentioning

confidence: 99%

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Schally

Nagy²

1999

European Journal of Endocrinology

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266

228

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In view of non-specific toxicity of most chemotherapeutic agents against normal cells, the development of targeted chemotherapy is warranted. Efficient targeting of chemotherapeutic drugs to the cancerous area could be of great benefit for patients with advanced or metastatic tumors. Targeted cytotoxic peptide conjugates are hybrid molecules composed of a peptide carrier which binds to receptors on tumors and a cytotoxic moiety. New cytotoxic analogs of LHRH, AN-152 in which doxorubicin (DOX) is linked to ]LHRH, and AN-207 which consists of 2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity binding and are much less toxic and more effective in vivo than their respective radicals in inhibiting tumor growth in LHRH receptor-positive models of human ovarian, mammary, or prostatic cancer. These results suggest that targeted cytotoxic LHRH analogs such as AN-207 could be considered for treatment of these cancers. The presence of receptors for bombesinlike peptides on a wide variety of tumors prompted us to use some of our bombesin/gastrin-releasing peptide antagonists as carrier molecules. Cytotoxic bombesin analogs, such as AN-215 containing AN-201, might find application in the treatment of small cell lung carcinoma (SCLC), and colorectal, gastric, pancreatic, mammary, and prostatic cancers. Since somatostatin receptors are found in various human neoplasms and the receptor subtypes to which octapeptide analogs bind with high affinity have been identified, we synthesized several cytotoxic somatostatin analogs including AN-162 and AN-238 containing DOX and 2-pyrrolino-DOX respectively, linked to octapeptide RC-121. Cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of human breast or prostate cancers expressing somatostatin receptors-2 and -5 and can be used for receptor-targeted chemotherapy. Cytotoxic somatostatin analogs might also find applications for the therapy of human pancreatic, colorectal, and gastric cancer as well as brain tumors and non-SCLC. Cytotoxic compounds linked to analogs of hormonal peptides like LHRH, bombesin, and somatostatin that can be targeted to certain tumors possessing receptors for those peptides could be an important addition to oncological armamentarium.

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Section: Design and Synthesis Of Targeted Cytotoxic Analogs Of Lhrhmentioning

confidence: 99%

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Schally

Nagy²

1999

European Journal of Endocrinology

Self Cite

266

228

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“…The isomerically pure model peptides obtained by HPLC can be useful to clarify the significance of this side reaction in the pharmacological behavior of the product. The formation of such isomer conjugates are known from previous studies [A Nagy et al, 1993] in the case of peptide hormones. The results presented here can be utilized predominantly to study comparatively the biological properties (e.g.…”

Section: Discussionmentioning

confidence: 99%

Pitfalls in the synthesis of fluorescent methotrexate oligopeptide conjugates

2016

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Pitfalls in the synthesis of fluorescent methotrexate containing oligopeptide conjugates M. Sebestyen et al. a) Unexpected cyclopeptide-formation with the lactonecarboxylic group of the Cf was detected, when Cf was attached to the α-amino group of the Lys residue on solid phase. This was avoided by changing the order of Cf incorporation with using Fmoc/Dde strategy. Alternatively, we have built the peptide with Fmoc strategy on solid phase first and performed the labelling with Cf-OSu subsequently in solution. Pitfalls in the synthesisb) During HF cleavage of the protected conjugates, MTX was demonstrated to form adducts with anisole and p-cresol scavengers, and the TMSOTf cleavage methodology was also found to be inadequate due to the large number of side products formed. We report here that using Fmoc/Dde strategy is an appropriate method to circumvent the cleavage with HF or TMSOTf. c) During the coupling of MTX with oligopeptide, structural and stereo isomers are formed. We have described here the suitable conditions of HPLC separation of these products. † Abbreviations: a: D-alanine, A: L-alanine

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“…25,26 The MTX molecule is conjugated to the carrier molecule through the g-carboxylic acid group of the glutamic acid residue to maintain its activity. 27 The a-carboxylic acid of MTX is necessary for binding to DHFR; thus, conjugation via the a-carboxylic acid is not desirable. To conjugate MTX to the carrier molecule, the a-carboxylic acid of the Glu residue is protected to give MTX-a-OtBu.…”

Section: Methotrexate (Mtx)mentioning

confidence: 99%

“…After coupling of the g-carboxylic acid with the N-terminal of the peptide carrier, the tertiary-butyl protecting group can be removed to give the desired conjugate. 27 …”

Section: Methotrexate (Mtx)mentioning

confidence: 99%

Peptide‐mediated targeted drug delivery

Majumdar

Siahaan

2010

Medicinal Research Reviews

132

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Targeted drug delivery to specific group of cells offers an attractive strategy to minimize the undesirable side effects and achieve the therapeutic effect with a lower dose. Both linear and cyclic peptides have been explored as trafficking moiety due to ease of synthesis, structural simplicity, and low probability of undesirable immunogenicity. Peptides derived from sequence of cell surface proteins, such as intercellular adhesion molecule-1 (ICAM-1), LHRH, Bombesin, and LFA-1, have shown potent binding affinity to the target cell surface receptors. Moreover, peptides derived from ICAM-1 receptor can be internalized by the leukemic T-cells along with the conjugated moiety offering the promise to selectively treat cancers and autoimmune diseases. Systematic analyses have revealed that physicochemical properties of the drug-peptide conjugates and their mechanism of receptor-mediated cellular internalization are important controlling factors for developing a successful targeting system. This review is focused on understanding the factors involved in the development of an effective drug-peptide conjugate with an emphasis on the chemistry and biology of the conjugates. Reported results on several promising drug-peptide conjugates have been critically evaluated. The approaches and results presented here will serve as a guide to systematically approach targeted delivery of cytotoxic drug molecules using peptides for treatment of several diseases.

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Selective coupling of methotrexate to peptide hormone carriers through a gamma-carboxamide linkage of its glutamic acid moiety: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate activation in salt coupling.

Cited by 28 publications

References 17 publications

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Pitfalls in the synthesis of fluorescent methotrexate oligopeptide conjugates

Peptide‐mediated targeted drug delivery

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