Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines

Abstract

In vitro evaluation of the halogenated pyrrolo[3,2-d]pyrimidines identified antiproliferative activities in compounds 1 and 2 against four different cancer cell lines. Upon screening of a series of pyrrolo[3, 2-d]pyrimidines, the 2,4-Cl compound 1 was found to exhibit antiproliferative activity at low micromolar concentrations. Introduction of iodine at C7 resulted in significant enhancement of potency by reducing the IC50 into sub-micromolar levels, thereby suggesting the importance of a halogen at C7. This finding was further supported by an increased antiproliferative effect for 4 as compared to 3. Cell-cycle and apoptosis studies conducted on the two potent compounds 1 and 2 showed differences in their cytotoxic mechanisms in triple negative breast cancer MDA-MB-231 cells, wherein compound 1 induced cells to accumulate at the G2/M stage with little evidence of apoptotic death. In contrast, compound 2 robustly induced apoptosis with concomitant G2/M cell cycle arrest in this cell model.

Anticancer Properties of Halogenated Pyrrolo[3,2‐d]pyrimidines with Decreased Toxicity via N5 Substitution

“…This was followed by a modified Batcho-Leimgruber indole synthesis to prepare enamine 3 . [9] The Batcho-Leimgruber process relies on the slight acidity of the 6-methyl group, which can be deprotonated to form a carbocation that is resonance stabilized by the nitro group. Nucleophilic attack on the dimethylacetal reagent results in formation of the amino side chain, which is deprotonated to result in the elimination product 3 .…”

“…[9] A structure-activity relationship (SAR) study found that compound 5 is a potent inhibitor of the TNBC MDA-MB-231 cell line, and further, caused an accumulation of cells in the G 2 /M stage without causing significant apoptosis. [9] These findings are consistent with earlier reports of other 9-deazapurines finding use as antiproliferative agents. [12] …”

“…The presence of the halogen also altered the apparent mechanism of action, with the majority of cells now undergoing apoptosis, although the mechanism is still unclear. [9] These findings led us to further investigate the effect of substituents on the pyrrole moiety of these compounds with the aim to retain or increase activity while decreasing toxicity. Compounds 5–9 were synthesized and subsequently evaluated for activity against multiple cancer cell lines.…”

Continuous‐Flow retro‐Diels–Alder Reaction: A Process Window for Designing Heterocyclic Scaffolds

“…Focussing on the biological potential of fused pyrimidinones, and continuing our work on the synthesis of new N‐heterocycles, we intended to further capitalize on the CF rDA protocol by synthesizing more complex pyrimidinone‐fused moieties in both racemic and enantiopure forms. Pyrrolopyrimidines have a wide range of applications in medicinal chemistry; they show antimicrobial, antitumor, antiasthmatic, antihypertensive, and anti‐inflammatory activities. Pyrimidoisoindoles show high vasorelaxtant,[26a] antiplasmodial,[26b] and antifungal actions.…”

Synthesis of Pyrrolo[1,2-a]pyrimidine Enantiomers via Domino Ring-Closure followed by Retro Diels-Alder Protocol

“…Pyrrolopyrimidines display a broad applicability in medicinal chemistry exhibiting antimicrobial [ 39 , 40 , 41 , 42 , 43 ], antitumour [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ], antiasthmatic [ 59 ], antihypertensive [ 60 ], and anti-inflammatory [ 61 ] activities. Several method have been developed for synthesizing pyrrolopyrimidines in the last few years [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ].…”