Synthesis and Biological Studies of c(RGDyK) Conjugates of Cucurbitacins

Chatzisideri, Theodora; Dalezis, Panagiotis; Leonidis, George; Bousis, Spyridon; Trafalis, Dimitrios T.; Bianchini, Francesca; Sarli, Vasiliki

doi:10.4155/fmc-2020-0309

Cited by 7 publications

(4 citation statements)

References 48 publications

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“…In previous research efforts by our group, the cyclic pentapeptide c(RGDyK), which is a potent integrin α v β 3 ligand, was employed for the targeted delivery of various anticancer drugs and bioactive molecules such as gemcitabine [ 22 ], the triterpenoids cucurbitacins [ 23 ], and platinum complexes [ 24 ]. c(RGDyK) peptide potently binds α v β 3 integrins (IC 50 = 3.8 ± 0.42 nM) and, less potently, α v β 5 (IC 50 = 503 ± 55 nM), α v β 6 (IC 50 = 86 ± 7 nM), and α 5 β 1 integrins (IC 50 = 236 ± 45 nM) [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Anti-Angiogenic Activity of Novel c(RGDyK) Peptide-Based JH-VII-139-1 Conjugates

et al. 2023

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Peptide–drug conjugates are delivery systems for selective delivery of cytotoxic agents to target cancer cells. In this work, the optimized synthesis of JH-VII-139-1 and its c(RGDyK) peptide conjugates is presented. The low nanomolar SRPK1 inhibitor, JH-VII-139-1, which is an analogue of Alectinib, was linked to the ανβ3 targeting oligopeptide c(RGDyK) through amide, carbamate and urea linkers. The chemostability, cytotoxic and antiangiogenic properties of the synthesized hybrids were thoroughly studied. All conjugates retained mid nanomolar-level inhibitory activity against SRPK1 kinase and two out of four conjugates, geo75 and geo77 exhibited antiproliferative effects with low micromolar IC50 values against HeLa, K562, MDA-MB231 and MCF7 cancer cells. The activities were strongly related to the stability of the linkers and the release of JH-VII-139-1. In vivo zebrafish screening assays demonstrated the ability of the synthesized conjugates to inhibit the length or width of intersegmental vessels (ISVs). Flow cytometry experiments were used to test the cellular uptake of a fluorescein tagged hybrid in MCF7 and MDA-MB231 cells that revealed a receptor-mediated endocytosis process. In conclusion, most conjugates retained the inhibitory potency against SRPK1 as JH-VII-139-1 and demonstrated antiproliferative and antiangiogenic activities. Further animal model experiments are needed to uncover the full potential of such peptide conjugates in cancer therapy and angiogenesis-related diseases.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Anti-Angiogenic Activity of Novel c(RGDyK) Peptide-Based JH-VII-139-1 Conjugates

et al. 2023

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“…18 Our group has conducted extensive studies synthesizing c(RGDyK) conjugates of known anticancer drugs for cancer imaging and treatment. We previously prepared c(RGDyK) conjugates of 5-FU, the alkylating agent POPAM, the natural products cucurbitacins, 19 and a Pt(II) complex for real-time drug delivery monitoring in cancer cells and photodynamic therapy (PDT). 20,21 It is known that the c(RGDyK) peptide has a high-affinity binding to α v β 3 integrins (IC 50 = 3.8 ± 0.42 nM) and has a lower binding to α v β 5 (IC 50 = 503 ± 55 nM), α v β 6 (IC 50 = 86 ± 7 nM), and α 5 β 1 integrins (IC 50 = 236 ± 45 nM).…”

Section: ■ Introductionmentioning

confidence: 99%

“…Our group has conducted extensive studies synthesizing c(RGDyK) conjugates of known anticancer drugs for cancer imaging and treatment. We previously prepared c(RGDyK) conjugates of 5-FU, the alkylating agent POPAM, the natural products cucurbitacins, and a Pt(II) complex for real-time drug delivery monitoring in cancer cells and photodynamic therapy (PDT). , It is known that the c(RGDyK) peptide has a high-affinity binding to α v β 3 integrins (IC 50 = 3.8 ± 0.42 nM) and has a lower binding to α v β 5 (IC 50 = 503 ± 55 nM), α v β 6 (IC 50 = 86 ± 7 nM), and α 5 β 1 integrins (IC 50 = 236 ± 45 nM) . Accumulative evidence demonstrates the association between integrin expression and the degree of dermal invasion in melanoma, risk of metastasis, and lung cancer. , In addition, melanoma tumors may metastasize to distant lymph nodes or other parts of the body such as the lung, liver, brain, and bone .…”

Section: Introductionmentioning

confidence: 99%

Integrin-Mediated Targeted Cancer Therapy Using c(RGDyK)-Based Conjugates of Gemcitabine

et al. 2021

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Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: c(RGDyK)-based conjugates of gemcitabine (GEM) with the carbonate and carbamate linkages in the 6-OH group of GEM were synthesized for the targeted delivery of GEM to integrin α v β 3 , overexpressing cancer cells to increase the stability as well as the tumor delivery of GEM and minimize common side effects associated with GEM treatment. Competitive cell uptake experiments demonstrated that conjugate TC113 could be internalized by A549 cells through integrin α v β 3 . Among the synthesized conjugates, TC113 bearing the carbamate linker was stable in human plasma and was further assessed in an in vivo pharmacokinetic study. TC113 appeared to be relatively stable, releasing GEM slowly into blood, while it showed potent antiproliferative properties against WM266.4 and A549 cells. The encouraging data presented in this study with respect to TC113 provide a promising keystone for further investigation of this GEM conjugate with potential future clinical applications.

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“…Our group has employed cyclic pentapeptide c(RGDyK), an integrin a v b 3 binder, for the targeted delivery of various anticancer drugs. We have observed promising anticancer activities after conjugation of triterpenoids cucurbitacins or platinum complexes to c(RGDyK). , Herein, we aimed to develop new antiangiogenic compounds based on the SRPK1 inhibitor SRPIN803. For this purpose, we have coupled SRPIN803 with c(RGDyK) and studied the properties of the new hybrid compounds.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of a c(RGDyK) Peptide Conjugate of SRPIN803

et al. 2021

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In the present study, SRPIN803 and c(RGDyK)-SRPIN803 hybrid compounds were efficiently synthesized and evaluated for their stability in human plasma and buffers of pH 7.4 and 5.2. The hybrids were mainly cytostatic against a panel of tested cancer cells, whereas one c(RGDyK)-SRPIN803 hybrid, geo35, was the most active compound in this screen and was cytotoxic against cell lines MCF7 and MRC5 with IC 50 values of 61 and 63 μM, respectively. SRPIN803 and geo35 exhibited antiangiogenic activity in zebrafish embryos, and this effect was dose-dependent. Although c(RGDyK)-SRPIN803 hybrid compounds were found less potent compared to SRPIN803, they have shown activities interesting enough to illustrate the potential of this approach for the development of a new class of antiangiogenic compounds.

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Synthesis and Biological Studies of c(RGDyK) Conjugates of Cucurbitacins

Cited by 7 publications

References 48 publications

Synthesis and Anti-Angiogenic Activity of Novel c(RGDyK) Peptide-Based JH-VII-139-1 Conjugates

Synthesis and Anti-Angiogenic Activity of Novel c(RGDyK) Peptide-Based JH-VII-139-1 Conjugates

Integrin-Mediated Targeted Cancer Therapy Using c(RGDyK)-Based Conjugates of Gemcitabine

Synthesis and Biological Evaluation of a c(RGDyK) Peptide Conjugate of SRPIN803

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