Synthesis and Biological Activity of 7-Oxo Substituted Analogues of 5-Deaza-5,6,7,8-tetrahydrofolic Acid (5-DATHF) and 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid (DDATHF)

Abstract

We recently described the syntheses of 12a-c, 4-amino-7-oxo substituted analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid (5-DATHF), and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF), in six steps from commercially available p-substituted methyl benzoates in 20-27% overall yields. Such analogues were tested in vitro against CCRF-CEM leukemia cells and showed that they are completely devoid of any activity, the IC(50) being higher than 20 microg/mL for all cases. To clarify if the presence of the carbonyl group in position C7, the distinctive feature of our synthetic methodology, is the reason for this lack of activity, we have now obtained the 7-oxo substituted analogues of 5-DATHF and DDATHF, 18a-c, in 10-30% overall yield. Testing of 18a-c in vitro against CCRF-CEM leukemia cells revealed that these compounds are totally inactive. A molecular modeling study of 18b inside the active site of the complex E. coliGARTFase-5-DATHF-GAR pointed to an electronic repulsion between the atoms of the 7-oxo group and the carbonyl group of Arg90 as a possible explanation for the inactivity of 18a-c.

A Diversity‐Oriented, Microwave‐Assisted Synthesis of 4‐oxo and 4‐chloropyrido[2,3‐d]pyrimidin‐7(8H)‐ones

“…The combined organic extracts were washed with water, dried (MgSO 4 ) and concentrated to give 20.52 g (0.123 mol, 41%) of 5{1} (R 1 H, R 2 Me, R 3 H) as a pale yellow solid. The spectral and analytical data were in agreement with authentic material [12b, 15,16].…”

“…As above for 10{1} but using 10.00 g (0.06 mol) of 2-methoxy-5-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carbonitrile (5{2}, R 1 Me, R 2 H, R 3 H) to yield 8.10 g (89%) of 10{2} (R 1 Me, R 2 H, R 3 H) as a white powder. The spectral and analytical data were in agreement with authentic material [12b, 15,16].…”

“…It is interesting to note that such 4-chloro substituted pyridopyrimidines 9 are perfectly stable even in water at reflux, consequently the practical impossibility to obtain compounds 9 by direct cyclization of amides 12 with HCl should be attributed to the hydrolysis of an intermediate caused by the water molecule lost during such process. (15) in 74% yield; this being, to the best of our knowledge, the first example of a Suzuki coupling on a pyridopyrimidine skeleton.…”

“…This behaviour was found to be independent of the nature and position of the substituents present on the pyridone ring. On the other hand, we described an acyclic variation of the above protocol for the synthesis of pyridopyrimidines (2, R 4 NH 2 ) based on the isolation of the corresponding Michael adduct (8, G CN) [15], that also allowed us to obtain 4-oxopyrido [2,3-d] From the preceding discussion it is clear that, so far, we were only capable to synthesize 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (2) with a carbon substituent at position C2 by using an amidine (6), which causes the presence of an amino group or a carbonyl group at C4 of the resulting pyrido [2,3-d]pyrimidine. Now, as a part of our ongoing research in the area of combinatorial chemistry focused on the preparation of random libraries for High Throughput Screening (HTS), we decided to devise a strategy to synthesize 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (9) bearing a carbon substituent at C2 and a chlorine atom at C4 (R 4 Cl), susceptible of subsequent decoration chemistry (reduction, nucleophilic displacement with amines, C À C bond formation).…”

The Relevance of Polar Surface Area (PSA) in Rationalizing Biological Properties of Severalcis‐Diamminemalonatoplatinum(II) Derivatives

“…The use of carbodiimide-based coupling agents, such as dicyclohexylcarbodiimide (DCC) [15,16] and 1- [3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDC), [17] as well as diphenylphosphoryl azide (DPPA) [18] and diethyl cyanophosphonate (DECP), [19,20] resulted in a number of byproducts and/or poor yield. Therefore, we followed the method developed by Kamiń ski (see Supporting Information), which proved to be successful in the synthesis of peptide bonds.…”