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

Makale detayları

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

Yazarlar:

M. Mustafa Çetin

Yayıncı:

Giresun University

Ana Başlıklar:

Yapısal Biyoloji

Dergi:

Karadeniz Fen Bilimleri Dergisi Vol.14 Issue 1, pp.359-390

Belge Tipi:

Makale

Yayın Tarihi:

3/2024

Belge Dili:

İngilizce

Document ID (Org No.):

2001313224

pISSN:

2564-7377

Anahtar kelimeler:

Özet:

 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 drugsAPIs 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 drugsAPIs 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 kcalmol and inhibition constants ranging from 225 to 569 nM against HDAC1 andor 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 Lipinskis rule of five, providing outstanding therapeutic potential for the breast cancer brain metastasis.

 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 drugsAPIs 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 drugsAPIs 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 kcalmol and inhibition constants ranging from 225 to 569 nM against HDAC1 andor 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 Lipinskis rule of five, providing outstanding therapeutic potential for the breast cancer brain metastasis.

 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 drugsAPIs 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 drugsAPIs 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 kcalmol and inhibition constants ranging from 225 to 569 nM against HDAC1 andor 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 Lipinskis rule of five, providing outstanding therapeutic potential for the breast cancer brain metastasis.

 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 veveya aktif farmasötik maddelerin geliştirilmesi artan bir taleptir. Bu çalışmada, mTOR ve HDAC enzimlerine karşı oldukça güçlü antikanser terapötik ilaçlar veveya 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 veveya mTOR enzimlerine karşı 9.4 ile 7.1 kcalmol 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 Lipinskinin beş kuralına göre ADMET çalışmasıyla da desteklenmiş olup, meme kanseri beyin metastazına sahip hastalar için olağanüstü bir terapötik potansiyel sağlamaktadır.

Makale detayları

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

Yazarlar:

M. Mustafa Çetin

Yayıncı:

Giresun University

Ana Başlıklar:

Yapısal Biyoloji

Dergi:

Karadeniz Fen Bilimleri Dergisi Vol.14 Issue 1, pp.359-390

Belge Tipi:

Makale

Yayın Tarihi:

3/2024

Belge Dili:

İngilizce

Document ID (Org No.):

2001313224

pISSN:

2564-7377

Anticancer therapeutic drugs/APIs

breast cancer brain metastases

mTOR

HDAC

1

10-phenanthroline

prodigiosinAntikanser tedavi edici ilaçlar/aktif farmasötik maddeler

meme kanseri beyin metastazları

mTOR

HDAC

1

10-fenantrolin

prodigiosin

Sayı

Makale detayları

Yazarlar: M. Mustafa Çetin

Yayıncı: Giresun University

Ana Başlıklar: Yapısal Biyoloji

Dergi: Karadeniz Fen Bilimleri Dergisi Vol.14 Issue 1, pp.359-390

Belge Tipi: Makale

Yayın Tarihi: 3/2024

Belge Dili: İngilizce

Document ID (Org No.): 2001313224

pISSN: 2564-7377

Sayı

Yazarlar:

M. Mustafa Çetin

Yayıncı:

Giresun University

Ana Başlıklar:

Yapısal Biyoloji

Dergi:

Karadeniz Fen Bilimleri Dergisi Vol.14 Issue 1, pp.359-390

Belge Tipi:

Makale

Yayın Tarihi:

3/2024

Belge Dili:

İngilizce

Document ID (Org No.):

2001313224

pISSN:

2564-7377