Design, synthesis, and biological evaluation of new thieno[2,3-d] pyrimidine derivatives as targeted therapy for PI3K...

Area of Science:

• Medicinal Chemistry
• Oncology
• Biochemistry

Background:

• Cancer is characterized by uncontrolled cell growth, with phosphatidylinositol 3-kinase (PI3K) signaling pathways playing a crucial role in its progression.
• Targeting PI3K offers a promising strategy for developing novel anti-cancer therapeutics.

Purpose of the Study:

• To design and synthesize novel morpholine-based thieno[2,3-d]pyrimidine derivatives as potential inhibitors of PI3K.
• To evaluate the antiproliferative and enzymatic inhibitory activities of these novel compounds against PI3K isoforms and cancer cell lines.

Main Methods:

• Synthesis of 28 morpholine-based thieno[2,3-d]pyrimidine derivatives.
• Evaluation of antiproliferative activity using the NCI 60 cell line panel.
• Assessment of enzymatic inhibitory activity against PI3K isoforms.
• Molecular docking studies into the PI3K active site.

Main Results:

• Three synthesized compounds demonstrated significant cytotoxic effects against breast cancer cell lines, notably T-47D.
• Compound VIb displayed potent enzymatic inhibition against PI3Kβ (72%) and PI3Kγ (84%).
• Compound VIb also showed broad activity across various NCI cell lines, especially those with overexpressed PI3K, and exhibited a binding mode similar to PI-103.

Conclusions:

• The novel morpholine-based thieno[2,3-d]pyrimidine derivatives show promise as anti-cancer agents targeting PI3K.
• Compound VIb represents a lead candidate for further optimization as a new chemical entity for cancer therapy.