Design and Synthesis of New bis-oxindole and Spiro(triazole-oxindole) as CDK4 Inhibitors with Potent Anti-breast Cancer Activity
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
BACKGROUND: Since CDKs have been demonstrated to be overexpressed in a wide spectrum of human malignancies, their inhibition has been cited as an effective technique for anticancer drug development.
METHODS: In this context, new bis-oxindole/spiro-triazole-oxindole anti-breast cancer drugs with potential CDK4 inhibitory effects were produced in this work. The novel series of bis-oxindole/spirotriazole- oxindole were synthesized from the reaction of bis-oxindole with the aniline derivatives then followed by 1,3-dipolar cycloaddition of hydrazonoyl chloride.
RESULTS: The structure of these bis-oxindole/spiro-triazole-oxindole series was proven based on their spectral analyses. Most bis-oxindole and bis-spiro-triazole-oxindole compounds effectively inhibited the growth of MCF-7 (IC50 = 2.81-17.61 μM) and MDA-MB-231 (IC50 = 3.23-7.98 μM) breast cancer cell lines with low inhibitory activity against normal WI-38 cells. While the reference doxorubicin showed IC50 values of 7.43 μM against MCF-7 and 5.71 μM against the MDA-MB-231 cell line. Additionally, compounds 3b, 3c, 6b, and 6d revealed significant anti-CDK4 activity (IC50 = 0.157- 0.618 μM) compared to palbociclib (IC50 = 0.071 μM). Subsequent mechanistic investigations demonstrated that 3c was able to trigger tumor cell death through the induction of apoptosis. Moreover, it stimulated cancer cell cycle arrest in the G1 phase. Furthermore, western blotting disclosed that the 3c-induced cell cycle arrest may be mediated through p21 upregulation.
CONCLUSION: According to all of the findings, bis-oxindole 3c shows promise as a cancer treatment targeting CDK4.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:20 |
|---|---|
| Enthalten in: |
Medicinal chemistry (Shariqah (United Arab Emirates)) - 20(2024), 1 vom: 19., Seite 63-77 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Farghaly, Thoraya A [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 30.01.2024 Date Revised 30.01.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.2174/1573406419666230810124855 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM362207909 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM362207909 | ||
| 003 | DE-627 | ||
| 005 | 20240130232034.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.2174/1573406419666230810124855 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1275.xml |
| 035 | |a (DE-627)NLM362207909 | ||
| 035 | |a (NLM)37723960 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Farghaly, Thoraya A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design and Synthesis of New bis-oxindole and Spiro(triazole-oxindole) as CDK4 Inhibitors with Potent Anti-breast Cancer Activity |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 30.01.2024 | ||
| 500 | |a Date Revised 30.01.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a BACKGROUND: Since CDKs have been demonstrated to be overexpressed in a wide spectrum of human malignancies, their inhibition has been cited as an effective technique for anticancer drug development | ||
| 520 | |a METHODS: In this context, new bis-oxindole/spiro-triazole-oxindole anti-breast cancer drugs with potential CDK4 inhibitory effects were produced in this work. The novel series of bis-oxindole/spirotriazole- oxindole were synthesized from the reaction of bis-oxindole with the aniline derivatives then followed by 1,3-dipolar cycloaddition of hydrazonoyl chloride | ||
| 520 | |a RESULTS: The structure of these bis-oxindole/spiro-triazole-oxindole series was proven based on their spectral analyses. Most bis-oxindole and bis-spiro-triazole-oxindole compounds effectively inhibited the growth of MCF-7 (IC50 = 2.81-17.61 μM) and MDA-MB-231 (IC50 = 3.23-7.98 μM) breast cancer cell lines with low inhibitory activity against normal WI-38 cells. While the reference doxorubicin showed IC50 values of 7.43 μM against MCF-7 and 5.71 μM against the MDA-MB-231 cell line. Additionally, compounds 3b, 3c, 6b, and 6d revealed significant anti-CDK4 activity (IC50 = 0.157- 0.618 μM) compared to palbociclib (IC50 = 0.071 μM). Subsequent mechanistic investigations demonstrated that 3c was able to trigger tumor cell death through the induction of apoptosis. Moreover, it stimulated cancer cell cycle arrest in the G1 phase. Furthermore, western blotting disclosed that the 3c-induced cell cycle arrest may be mediated through p21 upregulation | ||
| 520 | |a CONCLUSION: According to all of the findings, bis-oxindole 3c shows promise as a cancer treatment targeting CDK4 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CDK4 inhibitors | |
| 650 | 4 | |a anti-breast cancer activity | |
| 650 | 4 | |a bis-oxindole | |
| 650 | 4 | |a bis-spiro(triazole-oxindole) | |
| 650 | 4 | |a cancer cell. | |
| 650 | 4 | |a docking study | |
| 650 | 7 | |a Triazoles |2 NLM | |
| 650 | 7 | |a Oxindoles |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a CDK4 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.22 |2 NLM | |
| 650 | 7 | |a Cyclin-Dependent Kinase 4 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.22 |2 NLM | |
| 700 | 1 | |a Pashameah, Rami A |e verfasserin |4 aut | |
| 700 | 1 | |a Bayazeed, Abrar |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Soliemy, Amerah M |e verfasserin |4 aut | |
| 700 | 1 | |a Alsaedi, Amani M R |e verfasserin |4 aut | |
| 700 | 1 | |a Harras, Marwa F |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Medicinal chemistry (Shariqah (United Arab Emirates)) |d 2005 |g 20(2024), 1 vom: 19., Seite 63-77 |w (DE-627)NLM163628467 |x 1875-6638 |7 nnns |
| 773 | 1 | 8 | |g volume:20 |g year:2024 |g number:1 |g day:19 |g pages:63-77 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.2174/1573406419666230810124855 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 20 |j 2024 |e 1 |b 19 |h 63-77 | ||