Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients

M. Mustafa Çetin; Sümeyye Berfin Gül

doi:10.31466/kfbd.1423254

EN TR

Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients

Öz

Breast cancer is considered as a leading cancer type with the secondary highest possibility of brain metastasis. Most research in breast cancer is currently directed into the mortality of brain metastatic breast cancer. However, there is no effective treatment or anticancer therapeutics specifically for this cancer type. Hence, development of effective and novel anticancer therapeutic drugs/APIs to inhibit HDAC and mTOR, playing very important role on modulating breast cancer progression is an increasing demand. In this study, the structure-activity relationship and in silico modeling of a series of prodigiosin and 1,10-phenanthroline derivatives as highly potent anticancer therapeutic drugs/APIs against mTOR and HDAC enzymes have been investigated. Compared to the natural product Ps, 20 of the highly potent ligands, especially 2a, 6b, 13 and 13a, have exhibited very promising binding energies ranging from –9.4 to –7.1 kcal/mol and inhibition constants ranging from 225 to 569 nM against HDAC1 and/or mTOR enzymes. Ligands 2a, 5, 6b, 7b and 13 in particular show effective dual action against both enzymes. The findings from the in silico modeling studies have also been supported with MD simulations and ADMET study with Lipinski’s rule of five, providing outstanding therapeutic potential for the breast cancer brain metastasis.

Anahtar Kelimeler

Anticancer therapeutic drugs/APIs, breast cancer brain metastases, mTOR, HDAC, 1, 10-phenanthroline, prodigiosin

Bir Dizi Prodigiosin ve 1,10-Fenantrolin Türevlerinin Yeni Nesil Etkin Antikanser Tedavi Edici İlaçlar ya da Aktif Farmasötik Maddeler Olarak Tasarımı ve Yapısal İncelenmesi

Öz

Meme kanseri, beyin metastazı olasılığı en yüksek olan ikinci kanser türü olarak kabul edilmektedir. Bu yüzden meme kanseriyle ilgili araştırmaların çoğu beyin metastatik meme kanserinin mortalitesine yöneliktir. Ancak bu kanser türüne özgü etkili bir tedavi veya antikanser tedavi yöntemi mevcut değildir. Bu nedenle, meme kanseri ilerlemesinin modüle edilmesinde çok önemli rol oynayan HDAC ve mTOR enzimlerini inhibe edecek etkili ve yeni nesil antikanser terapötik ilaçların ve/veya aktif farmasötik maddelerin geliştirilmesi artan bir taleptir. Bu çalışmada, mTOR ve HDAC enzimlerine karşı oldukça güçlü antikanser terapötik ilaçlar ve/veya aktif farmasötik maddeler olarak bir dizi prodigiosin ve 1,10-fenantrolin türevinin yapı-aktivite ilişkisi ve in silico modellemesi incelenmiştir. Doğal ürün Ps ile karşılaştırıldığında, bu ligandlardan 20 tanesi, özellikle 2a, 6b, 13 ve 13a, HDAC1 ve/veya mTOR enzimlerine karşı –9.4 ile –7.1 kcal/mol arasında değişen çok umut verici bağlanma enerjileri ve 225 ile 569 nM arasında değişen inhibisyon sabitleri sergilemiştir. Özellikle 2a, 5, 6b, 7b ve 13 her iki enzime karşı iki taraflı etkinlik (dual action) göstermiştir. İn silico modelleme çalışmalarından elde edilen bulgular, MD simülasyonları ve Lipinski'nin beş kuralına göre ADMET çalışmasıyla da desteklenmiş olup, meme kanseri beyin metastazına sahip hastalar için olağanüstü bir terapötik potansiyel sağlamaktadır.

Anahtar Kelimeler

Antikanser tedavi edici ilaçlar/aktif farmasötik maddeler, meme kanseri beyin metastazları, mTOR, HDAC, 1, 10-fenantrolin, prodigiosin

Destekleyen Kurum

Kadir Has University

Proje Numarası

MMC_BAF and MMC_SEED

Etik Beyan

The author declares that this study complies with Research and Publication Ethics.

Teşekkür

Financial support from the Kadir Has University (MMC_BAF and MMC_SEED) is gratefully acknowledged. This research was also supported by Kadir Has University computer laboratories and facilities for the computational and molecular modeling studies. We greatly thank Prof. Kemal Yelekci and his graduate student Damla Dere from Kadir Has University and appreciate for their support to conduct our computational and molecular modeling studies on their computers as well as endless support in the discussion of the obtained results.

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Ayrıntılar

Birincil Dil

İngilizce

Konular

Yapısal Biyoloji

Bölüm

Araştırma Makalesi

Yazarlar

M. Mustafa Çetin ^*
0000-0002-6443-0232
Türkiye

Sümeyye Berfin Gül Bu kişi benim
0009-0008-7474-3516
Türkiye

Yayımlanma Tarihi

15 Mart 2024

Gönderilme Tarihi

21 Ocak 2024

Kabul Tarihi

14 Mart 2024

Yayımlandığı Sayı

Yıl 2024 Cilt: 14 Sayı: 1

DOI

https://doi.org/10.31466/kfbd.1423254

IZ

https://izlik.org/JA89DD63LJ

APA

Çetin, M. M., & Gül, S. B. (2024). Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients. Karadeniz Fen Bilimleri Dergisi, 14(1), 359-390. https://doi.org/10.31466/kfbd.1423254

AMA

1.Çetin MM, Gül SB. Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients. KFBD. 2024;14(1):359-390. doi:10.31466/kfbd.1423254

Chicago

Çetin, M. Mustafa, ve Sümeyye Berfin Gül. 2024. “Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients”. Karadeniz Fen Bilimleri Dergisi 14 (1): 359-90. https://doi.org/10.31466/kfbd.1423254.

EndNote

Çetin MM, Gül SB (01 Mart 2024) Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients. Karadeniz Fen Bilimleri Dergisi 14 1 359–390.

IEEE

[1]M. M. Çetin ve S. B. Gül, “Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients”, KFBD, c. 14, sy 1, ss. 359–390, Mar. 2024, doi: 10.31466/kfbd.1423254.

ISNAD

Çetin, M. Mustafa - Gül, Sümeyye Berfin. “Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients”. Karadeniz Fen Bilimleri Dergisi 14/1 (01 Mart 2024): 359-390. https://doi.org/10.31466/kfbd.1423254.

JAMA

1.Çetin MM, Gül SB. Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients. KFBD. 2024;14:359–390.

MLA

Çetin, M. Mustafa, ve Sümeyye Berfin Gül. “Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients”. Karadeniz Fen Bilimleri Dergisi, c. 14, sy 1, Mart 2024, ss. 359-90, doi:10.31466/kfbd.1423254.

Vancouver

1.M. Mustafa Çetin, Sümeyye Berfin Gül. Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients. KFBD. 01 Mart 2024;14(1):359-90. doi:10.31466/kfbd.1423254

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Design and Structural Investigation of a Series of Prodigiosin and 1,10-Phenanthroline Derivatives as Novel and Highly Potent Anticancer Therapeutic Drugs or Active Pharmaceutical Ingredients

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Bir Dizi Prodigiosin ve 1,10-Fenantrolin Türevlerinin Yeni Nesil Etkin Antikanser Tedavi Edici İlaçlar ya da Aktif Farmasötik Maddeler Olarak Tasarımı ve Yapısal İncelenmesi

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