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. 2025 Jul 10;30(14):2917.
doi: 10.3390/molecules30142917.

Pyrrolopyrimidines: Design, Synthesis and Antitumor Properties of Novel Tricyclic Pyrrolo [2,3- d]pyrimidine Derivatives

Buer Song  1 , Zarifa Murtazaeva  2 , Lifei Nie  1 , Rustamkhon Kuryazov  3 , Shukhrat Gaybullaev  2 , Chao Niu  1 , Khurshed Bozorov  1   2 , Haji Akber Aisa  1 , Jiangyu Zhao  1
Affiliations

Pyrrolopyrimidines: Design, Synthesis and Antitumor Properties of Novel Tricyclic Pyrrolo [2,3- d]pyrimidine Derivatives

Buer Song et al. Molecules. .

Abstract

The pyrrolo[2,3-d]pyrimidine (7-deazapurine) scaffold is a unique heterocyclic system included in the composition of most nucleotides. In this study, series of the pyrrolo[2,3-d]pyrimidine-imines and 3-halo-substituted pyrrolo[2,3-d]pyrimidines were designed and prepared in high yields. Condensed pyrimidines are obtained via carbonyl-amine condensation and carbon-halogen bond formation. Pyrrolo[2,3-d]pyrimidine-imines containing a bromine substituent at position C-4 of the phenyl ring and azepine side-ring exhibited superior antitumor activity on the colon cancer HT-29 cell line; IC50 values were 4.55 and 4.01 µM, respectively. These results revealed an interesting pattern, where condensed pyrimidinones containing an azepine ring demonstrated selective antitumor activity on the colon cancer cell line HT-29. In addition, the molecular docking results suggest that compound 8g provided a thorough understanding of its interactions with the DDR2 active site. This could pave the way for further development and optimization of DDR-targeting drugs, contributing to advancements in cancer therapeutics. This lead compound may serve as design templates for further studies.

Keywords: 7-deazapurine; DDR2 receptor; HT-29 cell line; N-halosuccinimide; Tf2O; antitumor activity; carbonyl-amine condensation; molecular docking; pyrrolo[2,3-d]pyrimidine; pyrrolo[2,3-d]pyrimidine-imines.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Structures of pyrimidine-based inhibitors from the AZD series used in cancer treatment, and the pyrrolo[2,3-d]pyrimidines 8a–j and 10a–f synthesized in this work.
Figure 2
Figure 2
Natural-products-based derivatization.
Scheme 1
Scheme 1
Synthesis of pyrrolo[2,3-d]pyrimidine-imines 8a–j.
Scheme 2
Scheme 2
Synthesis of 3-halo-substituted pyrrolopyrimidinones 10a–f.
Figure 3
Figure 3
Crystal structure of compound 8c (CCDC: 2169282).
Figure 4
Figure 4
The SAR of the highly active compounds 8f and 8g.
Figure 5
Figure 5
Docking result (A) and the 2D diagram (B) of 8g with DDR2.
See this image and copyright information in PMC

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