Synthesis of Novel Protected Nα(ω-Drug) Amino Acid Building Units for Facile Preparation of Anticancer Drug-Conjugates

Gilad, Yossi; Waintraub, Sagiv; Albeck, Amnon; Gellerman, Gary

doi:10.1007/s10989-015-9509-1

Cited by 7 publications

(7 citation statements)

References 34 publications

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“…In another contribution, Gellerman and colleagues planned and put in practice an efficient and general synthetic approach to the preparation of RGD-based drug conjugates (and some NGR congeners) (not shown). [60] The synthesis of a number of Nα-protected drug-loaded amino acid building blocks was accomplished by functionalization at the remote ω-site of amino acids -lysine, serine, tyrosine, threonine, aspartate and glutamate -with anticancer active ingredients such as chlorambucil, camptothecin, deacetylcolchicine, among others. Four RGD-cyclopeptides bearing different amino acid-drug units were obtained by practical and efficient SPPS, evidencing their utility in fast parallel synthesis of collections of peptide-drug conjugates for rapid assessment of drug release profiles.…”

Section: Dual Conjugates Embedding Cleavable Linkersmentioning

confidence: 99%

“…In another contribution, Gellerman and colleagues planned and put in practice an efficient and general synthetic approach to the preparation of RGD‐based drug conjugates (and some NGR congeners) (not shown) [60] . The synthesis of a number of Nα‐protected drug‐loaded amino acid building blocks was accomplished by functionalization at the remote ω‐site of amino acids – lysine, serine, tyrosine, threonine, aspartate and glutamate – with anticancer active ingredients such as chlorambucil, camptothecin, deacetylcolchicine, among others.…”

Section: Dual Conjugates Embedding Cleavable Linkersmentioning

confidence: 99%

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RGD Peptide‐Drug Conjugates as Effective Dual Targeting Platforms: Recent Advances

et al. 2021

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In recent years, targeted therapies have raised increasing interest as effective strategies to improve therapeutic efficiency, reduce the impact of adverse side effects, and overcome drug resistance, particularly in the field of cancer chemotherapeutics. Many examples of RGD (Arg‐Gly‐Asp) peptide‐drug conjugates (PDCs) have been proposed as targeted drug delivery systems. These molecular hybrids embody high affinity ligands targeting disease signatures (overexpressed integrin receptors or specific integrin‐related pathways within diseased cells/tissues) connected to recognized therapeutic units by means of carefully designed linker‐spacer combinations, to ultimately control stability, physico‐chemical properties, timing, and localization of drug release. This account has collected and critically surveyed relevant contributions from the period of 2015 to the present day, wishing to provide a window open on new synthesis strategies facing the challenging issues of site‐selective drug delivery and dual drug targeting.

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Section: Dual Conjugates Embedding Cleavable Linkersmentioning

confidence: 99%

Section: Dual Conjugates Embedding Cleavable Linkersmentioning

confidence: 99%

RGD Peptide‐Drug Conjugates as Effective Dual Targeting Platforms: Recent Advances

et al. 2021

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“…[280] Compared to protease-cleavable linkers (Chapters 2.3.1 and 4.1.1), the recognition site of esterase-cleavable linker systems is very short and in most cases non-peptidic; thus, warheads are mostly directly bound to the homing device via amino acids side chains or short spacers. For example, Gilad et al [281,282] developed conjugates with different cyclic peptides (c[RGDfX]) connected to different drugs by straightforward ester bond formation (Table 4.2, entries 1 and 2; Figure 4.5).…”

Section: Esterase Cleavable Pdcs and Smdcsmentioning

confidence: 99%

“…[175,292] Noteworthily, there is no great difference between carboxylic esters and carbamates in anti-proliferative activity where this effect is also independent of the corresponding drug. [281,282] Additionally, Gilad et al [283] synthesised c(RGDfK)-containing conjugates loaded with two drugs (both CLB or CPT and also a mixed one) (Table 4.2, entry 3). The payloads were connected via amides, esters, or carbamates, whereas the conjugate carrying two CLB one was bound by an amide and the second one by an ester bond showed the lowest chemostability under basic and acidic conditions (pH 7.4 and 5.2).…”

Section: Esterase Cleavable Pdcs and Smdcsmentioning

confidence: 99%

Small molecule– and peptide–drug conjugates addressing integrins: A story of targeted cancer treatment

Paulus,

Sewald

2024

Journal of Peptide Science

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Targeted cancer treatment should avoid side effects and damage to healthy cells commonly encountered during traditional chemotherapy. By combining small molecule or peptidic ligands as homing devices with cytotoxic drugs connected by a cleavable or non‐cleavable linker in peptide–drug conjugates (PDCs) or small molecule–drug conjugates (SMDCs), cancer cells and tumours can be selectively targeted. The development of highly affine, selective peptides and small molecules in recent years has allowed PDCs and SMDCs to increasingly compete with antibody‐drug conjugates (ADCs). Integrins represent an excellent target for conjugates because they are overexpressed by most cancer cells and because of the broad knowledge about native binding partners as well as the multitude of small‐molecule and peptidic ligands that have been developed over the last 30 years. In particular, integrin αVβ3 has been addressed using a variety of different PDCs and SMDCs over the last two decades, following various strategies. This review summarises and describes integrin‐addressing PDCs and SMDCs while highlighting points of great interest.

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“…Gilad, Y., et al [ 73 ] prepared novel peptide–camptothecin conjugates ( Figure 16 ). A selective cytotoxicity of two representatives—one linear and one cyclic RGD—camptothecin conjugates were evaluated on α v β 3 integrin overexpressed cancer cell lines: H-1299 (human non-small cell lung carcinoma), PC-3 (human prostate cancer), and HEK-293 as a negative control.…”

Section: Camptothecinmentioning

confidence: 99%

Molecular Delivery of Cytotoxic Agents via Integrin Activation

Cirillo

Giacomini

2021

Cancers

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Integrins are cell adhesion receptors overexpressed in tumor cells. A direct inhibition of integrins was investigated, but the best inhibitors performed poorly in clinical trials. A gained attention towards these receptors arouse because they could be target for a selective transport of cytotoxic agents. Several active-targeting systems have been developed to use integrins as a selective cell entrance for some antitumor agents. The aim of this review paper is to report on the most recent results on covalent conjugates between integrin ligands and antitumor drugs. Cytotoxic drugs thus conjugated through specific linker to integrin ligands, mainly RGD peptides, demonstrated that the covalent conjugates were more selective against tumor cells and hopefully with fewer side effects than the free drugs.

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Synthesis of Novel Protected Nα(ω-Drug) Amino Acid Building Units for Facile Preparation of Anticancer Drug-Conjugates

Cited by 7 publications

References 34 publications

RGD Peptide‐Drug Conjugates as Effective Dual Targeting Platforms: Recent Advances

RGD Peptide‐Drug Conjugates as Effective Dual Targeting Platforms: Recent Advances

Small molecule– and peptide–drug conjugates addressing integrins: A story of targeted cancer treatment

Molecular Delivery of Cytotoxic Agents via Integrin Activation

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