CycloSal-phosphate pronucleotides of cytostatic 6-(Het)aryl-7-deazapurine ribonucleosides: Synthesis, cytostatic activity, and inhibition of adenosine kinases.
A series of cycloSal-phosphate prodrugs of a recently described new class of nucleoside cytostatics (6-hetaryl-7-deazapurine ribonucleosides) was prepared. The corresponding 2',3'-isopropylidene 6-chloro-7-deazapurine nucleosides were converted into 5-O'-cycloSal-phosphates. These underwent a series of Stille or Suzuki cross-couplings with diverse (het)arylstannanes or -boronic acids to yield the protected 6-(het)aryl-7-deazapurine pronucleotides that were subsequently deprotected to give 12 derivatives of free pronucleotides. The in vitro cytostatic effect of the pronucleotides was compared with parent nucleoside analogues. In most cases, the activity of the pronucleotide was similar to or somewhat lower than that of the corresponding parent nucleosides, with the exception of 7-fluoro pronucleotides 13 a, 13 b, and 13 d, which had exhibited GIC(50) values that were improved by one order of magnitude (to the low nanomolar range). The presence of a cycloSal-phosphate group also influenced selectivity toward various cell lines. Several pronucleotides were found which strongly inhibit human adenosine kinase but only weakly inhibit the MTB adenosine kinase.
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Prague, Czech Republic.
Pavla
P
Spácilová
Petr
P
Naus
Radek
R
Pohl
Ivan
I
Votruba
Jan
J
Snásel
Helena
H
Zábranská
Iva
I
Pichová
Ria
R
Ameral
Gabriel
G
Birkus
Tomás
T
Cihlár
Michal
M
Hocek
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D010710:Phosphates / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011685:Purine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011687:Purines / Q000737:chemistry*; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C512929:7-deazapurine; D054697:Cytostatic Agents; D010710:Phosphates; D011355:Prodrugs; D011685:Purine Nucleotides; D011687:Purines; D012263:Ribonucleosides; C553430:cyclo-(3-methylsaligenyl)ribofuranosyl-4-(2-furyl)-5-fluoro-7'H-pyrrolo(2,3-d)pyrimidine-5'-O-phosphate; C553431:cyclo-(3-methylsaligenyl)ribofuranosyl-4-(3-furyl)-5-fluoro-7'H-pyrrolo(2,3-d)pyrimidine-5'-O-phosphate; C553432:cyclo-(3-methylsaligenyl)ribofuranosyl-4-(3-thienyl)-5-fluoro-7'H-pyrrolo(2,3-d)pyrimidine-5'-O-phosphate; D000248:Adenosine Kinase