Trimetrexate: molecular structures and conformational similarities in two crystal forms

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Quinazoline antifolates are a class of drugs used in cancer chemotherapy.
• Understanding the precise three-dimensional structure of these compounds is essential for optimizing their efficacy and designing new analogs.
• Trimetrexate (TMQ) is a non-classical quinazoline antifolate with known therapeutic applications.

Purpose of the Study:

• To determine the crystal structure of trimetrexate (TMQ) in two different forms: TMQ acetate monohydrate and hydrated TMQ free base.
• To elucidate the molecular conformation and key structural features of TMQ in the solid state.
• To compare the TMQ structure with other known quinazoline antifolates.

Main Methods:

• X-ray crystallography was employed to determine the structures of TMQ acetate monohydrate and hydrated TMQ free base.
• Crystallographic data were analyzed to identify bond lengths, bond angles, and overall molecular geometry.
• Structural comparisons were made with related antifolate compounds.

Main Results:

• The crystal structures of TMQ acetate monohydrate and hydrated TMQ free base were successfully determined.
• Trimetrexate adopts an extended molecular conformation in both crystal forms.
• The quinazoline and phenyl rings within the TMQ molecule are oriented perpendicularly to each other.
• Protonation of TMQ in the acetate salt occurs at the N1 position.
• The observed TMQ conformation is comparable to that of quinespar and methotrexate.

Conclusions:

• The determined crystal structures provide detailed insights into the three-dimensional architecture of trimetrexate.
• The extended conformation and ring orientation are significant features for the drug's interaction with its biological targets.
• Structural similarities with other antifolates suggest conserved binding modes and can inform future drug development efforts.