Pyrimidines

Presented by
Ena Athaide
MSc-2,sem-3
Institute of Science ,Mumbai

 Nucleotides are the activated precursors of nucleic
acids.
 Necessary for the replication of the genome and the
transcription of the genetic information into RNA.
 ATP,GTP, serves as an energy source for most
biological processes.
 Nucleotide derivatives such as UDP-
glucose participate in biosynthetic processes such
as the formation of glycogen.
 Essential components of signal-transduction
pathways. Cyclic nucleotides such as
cyclic AMP and cyclic GMP are second messengers

 Derived from purine or pyrimidine

HN
C
N
CH
CH
C
O
O
H
1
2
3
4
5
6
N1 and carbons 4, 5 and 6 are derived from
Aspartate
C2 and N3 are derived from carbamoyl
phosphate(Glutamine+CO2)

2 ATP + HCO3
-
+ Glutamine + H2O
CO
O PO3
-2
NH2
Carbamoyl Phosphate
NH2
C
N
H
CH
CH2
C
COO
O
HO
O
Carbamoyl Aspartate
HN
C
N
H
CH
CH2
C
COO
O
O
Dihydroorotate
HN
C
N
H
C
CH
C
COO
O
O
Orotate
HN
C
N
C
CH
C
COO
O
O
HH
CH2
OH OH
H H
O
O2-
O3P

Orotidine-5'-monophosphate
(OMP)
HN
C
N
CH
CH
C
O
O
HH
CH2
OH OH
H H
O
O2-
O3P

Uridine Monophosphate
(UMP)
2 ADP +
Glutamate +
Pi
Carbamoyl
Phosphate
Synthetase II
Aspartate
Transcarbamoylase
(ATCase)
Aspartate
Pi
H2O
Dihydroorotase
Quinone
Reduced
Quinone
Dihydroorotate
Dehydrogenase
PRPP PPi
Orotate Phosphoribosyl
Transferase
CO2
OMP
Decarboxylase
Pyrimidine Synthesis

 Nucleoside monophosphate kinase catalyzes
transfer of Pi to UMP to form UDP; nucleoside
diphosphate kinase catalyzes transfer of Pi from
ATP to UDP to form UTP
 CTP formed from UTP via CTP Synthetase
driven by ATP hydrolysis
 Glutamine provides amide nitrogen for C4 in animals

 Physiologic reducing agent of RNR
 Cys pair can swap H atoms with disulfide formed
regenerate original enzyme
 Thioredoxin gets oxidized to disulfide
Oxidized Thioredoxin gets reduced by NADPH ( final electron acceptor)
mediated by thioredoxin reductase

 Aspartate transcarbamoylase is an important step in
pyrimidine biosynthesis, controlled by feedback
mechanism.
 Activated by ATP ,inhibited by UTP.
 Carbamoyl phosphate synthetase 2 is regulatory
enzyme of pyrimidine synthesis in animals.
 Activated by PRPP and ATP, inhibited by UMP and
CMP.

New Pyrimidine Compounds May Lead to Improved
Treatments for Childhood Brain Cancer
 Medulloblastoma, is the most common malignant
cancer in children. Src (short for sarcoma) is a family
of proto-oncogenic tyrosine kinases active in many
cancer tumors, including medulloblastoma.
 A recent study shows that pyrazolo-[3,4-d]—
pyrimidine-derivatives, designed to target Src, may
be effective in interfering with the cell cycle and
causing cancer cell death in medulloblastoma.
 Aim was to investigate the inhibitory effects of new
pyrimidine-derivatives

 Findings show that, in medulloblastoma cells,
pyrimidine derivatives can downregulate Src activity
and reduce cell proliferation and tumor progression
in vivo.
 This suggests that pyrimidine derivatives could be an
effective therapeutic strategy not only for the
treatment of medulloblastomas, but also for other
Src expressing tumors.
 Although better treatment regimens, including
surgery, chemotherapy and radiotherapy have
substantially improved survival, medulloblastoma
remains incurable in about one third of patients and
current treatments can cause toxic neurocognitive

 Compared with conventional chemotherapeutic
agents cisplatin and etoposide that are presently
used in medulloblastoma therapy, they found that
these pyrimidine derivatives show major inhibitory
effects on cell proliferation.
 Using these compounds with radiotherapy could
allow the reduction of radiation doses and,
consequently, the avoidance of radiotherapy-related
cognitive and endocrine toxic effects.
 Moreover, findings reveal that the pyrimidine
compounds showed synergistic effects when
combined with cisplatin and etoposide, suggesting
their possible use in association with chemotherapy.

 Attempts to further reduce the morbidity and
mortality associated with medulloblastoma have
been limited by the toxicity of conventional
treatments and the low permeability of the blood-
brain barrier (BBB), which restricts the entry of
hydrophilic and large liphophilic compounds into the
brain.
 Other Src inhibitors, currently in clinical trials for the
treatment of other pathologies, showed low efficacy
in the treatment of metastasis to the brain.
 Pyrimidine derivatives have liphophilic
characteristics, which enable them to pass through
the blood brain barrier more easily, representing an
other advantage of their use in medulloblastoma

 Besides the possible use of these pyrimidine
derivatives in the treatment of medulloblastoma,
these compounds could be useful to develop new
pharmacologic inhibitors to study the physiological
and oncogenic functions of Src.

 David. L.Nelson,Michael M
.Cox,Lehninger,principles of Biochemistry, 4th
edition.
 Prescot,Harley,Kein.Microbiology,McGraw.Hill
International edition.pg:240-242.
 U.Satyanarayana,U.Chakrapani.Biochemistry,3rd
edition,pg:398-400.
 A.Rossi,S.Schenone,A.Angelucci,M.Cozzi ,V.Car
acciolo,F.Pentimalli,A.Puca,B.Pucci,R.Montagna
,M. Bologna,M.Botta,A.Giordano, New pyrazolo-
[3,4-d]-pyrimidinederivative Src kinase
inhibitors lead to cell cycle arrest and tumor
growth reduction of human medulloblastoma

Pyrimidines

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Pyrimidines