LEUCOVORIN


Synonyms	Leucovorin
Status
Molecule Category	Free-form
UNII	Q573I9DVLP
EPA CompTox	DTXSID0048216


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	VVIAGPKUTFNRDU-ABLWVSNPSA-N
Smiles	Nc1nc(=O)c2c([nH]1)NCC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)N2C=O
InChI	InChI=1S/C20H23N7O7/c21-20-25-16-15(18(32)26-20)27(9-28)12(8-23-16)7-22-11-3-1-10(2-4-11)17(31)24-13(19(33)34)5-6-14(29)30/h1-4,9,12-13,22H,5-8H2,(H,24,31)(H,29,30)(H,33,34)(H4,21,23,25,26,32)/t12?,13-/m0/s1

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C20H23N7O7
Molecular Weight	473.45
AlogP	-0.73
Hydrogen Bond Acceptor	9.0
Hydrogen Bond Donor	7.0
Number of Rotational Bond	10.0
Polar Surface Area	219.84
Molecular species	ACID
Aromatic Rings	2.0
Heavy Atoms	34.0

Reference

Journal : J. Med. Chem.

Title : Synthesis and biological activity of N omega-hemiphthaloyl-alpha,omega- diaminoalkanoic acid analogues of aminopterin and 3',5-dichloroaminopterin.

PubMed ID : 8035423

DOI : 10.1021/jm00040a008

Year : 1994

Volume : 37

Issue : 14

First Page : 2167

Last Page : 2174

Authors : Rosowsky A, Bader H, Wright JE, Keyomarsi K, Matherly LH.

Abstract : Analogues of N alpha-(4-amino-4-deoxypteroyl)-N delta-(hemiphthaloyl)-L-ornithine (PT523) with 3',5'-dichloro substitution in the p-aminobenzoyl moiety or with one less or one more CH2 group in the amino acid moiety were synthesized and tested as inhibitors of dihydrofolate reductase (DHFR) activity and cell growth. Replacement of L-ornithine in PT523 by L-2,4-diaminobutanoic acid or L-lysine did not decrease binding to human recombinant DHFR but resulted in some loss of activity against SCC25 human and SCC VII murine squamous cell carcinoma and against MCF-7 human breast carcinoma in culture. PT523 was several times more potent than methotrexate (MTX), aminopterin (AMT), or trimetrexate (TMQ). 3',5'-Dichloro substitution did not decrease either DHFR binding or cytotoxicity. A new synthetic route to PT523 from 2,4-diamino-6-(hydroxymethyl)pteridine and methyl N alpha-(4-aminobenzoyl)-N delta-phthaloyl-L-ornithinate was investigated but was not found superior to previously described methods. In comparative experiments on the ability of PT523 and MTX to competitively inhibit the influx of (6R)-5,10-dideazatetra-hydrofolate (DDATHF, lometrexol), used here as a surrogate for MTX and reduced folates, the Ki of PT523 was lower than that of MTX in both wild-type CCRF-CEM human leukemic lymphoblasts and the transport- and polyglutamylation-defective subline CEM/MTX. The CCRF-CEM cells were 10-fold more sensitive to PT523 than to MTX, whereas the CEM/MTX cells were 240-fold more sensitive. However, in contrast to other MTX-resistant cells where collateral sensitivity to PT523 has been seen. CEM/MTX cells still showed substantial cross resistance to PT523 which may reflect an unusual heightened ability to utilize exogenous folic acid. The good correlation observed with both cell lines between the cytotoxicity of PT523 and MTX and the ability to inhibit DDATHF influx supported the view that PT523 and MTX share, at least in part, a common protein carrier for membrane transport.

Reference

Journal : J. Med. Chem.

Title : Synthesis and discovery of high affinity folate receptor-specific glycinamide ribonucleotide formyltransferase inhibitors with antitumor activity.

PubMed ID : 18680275

DOI : 10.1021/jm8003366

Year : 2008

Volume : 51

Issue : 16

First Page : 5052

Last Page : 5063

Authors : Deng Y, Wang Y, Cherian C, Hou Z, Buck SA, Matherly LH, Gangjee A.

Abstract : 6-Substituted classical pyrrolo[2,3-d]pyrimidine antifolates with a three- to six-carbon bridge between the heterocycle and the benzoyl-L-glutamate (compounds 2-5, respectively) were synthesized starting from methyl 4-formylbenzoate and a Wittig reaction with the appropriate triphenylphosphonium bromide, followed by reduction and conversion to the alpha-bromomethylketones. Cyclocondensation of 2,4-diamino-4-oxopyrimidine with the alpha-bromoketones, coupling with diethyl-L-glutamate, and saponification afforded 2-5. Compounds 2-5 had negligible substrate activity for RFC but showed variably potent (nanomolar) and selective inhibitory activities toward Chinese hamster ovary cells that expressed FRalpha or FRbeta and toward FRalpha-expressing KB and IGROV1 human tumor cells. Inhibition of KB cell colony formation was also observed. Glycinamide ribonucleotide formyl transferase (GARFTase) was identified as the primary intracellular target of the pyrrolo[2,3-d]pyrimidines. The combined properties of selective FR targeting, lack of RFC transport, and GARFTase inhibition resulting in potent antitumor activity are unprecedented and warrant development of these analogues as antitumor agents.

Reference

Journal : J. Med. Chem.

Title : Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitors of purine biosynthesis with selectivity for high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier for cellular entry.

PubMed ID : 20085328

DOI : 10.1021/jm9015729

Year : 2010

Volume : 53

Issue : 3

First Page : 1306

Last Page : 1318

Authors : Wang L, Cherian C, Desmoulin SK, Polin L, Deng Y, Wu J, Hou Z, White K, Kushner J, Matherly LH, Gangjee A.

Abstract : 2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl side chain and four to six carbon bridge lengths (compounds 1-3) were synthesized as substrates for folate receptors (FRs) and the proton-coupled folate transporter (PCFT). Conversion of acetylene carboxylic acids to alpha-bromomethylketones and condensation with 2,4-diamino-6-hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidines. Sonogashira coupling with (S)-2-[(5-bromo-thiophene-2-carbonyl)-amino]-pentanedioic acid diethyl ester, followed by hydrogenation and saponification, afforded 1-3. Compounds 1 and 2 potently inhibited KB and IGROV1 human tumor cells that express FR alpha, reduced folate carrier (RFC), and PCFT. The analogs were selective for FR and PCFT over RFC. Glycinamide ribonucleotide formyltransferase was the principal cellular target. In SCID mice with KB tumors, 1 was highly active against both early (3.5 log kill, 1/5 cures) and advanced (3.7 log kill, 4/5 complete remissions) stage tumors. Our results demonstrate potent in vitro and in vivo antitumor activity for 1 due to selective transport by FRs and PCFT over RFC.

Assay Description	Organism	Bioactivity
Tested for inhibition of [14C]-DDATHF influx in CEM/MTX cells of human leukemic lymphoblasts	Homo sapiens	740.0 nM
Inhibition of human RFC-mediated [3H]MTX transport in Chinese hamster PC43-10 cells at 10 uM	Homo sapiens	60.0 %
Displacement of [3H]MTX from human RFC expressed in Chinese hamster PC43-10 cells at 10 uM	Homo sapiens	50.0 %

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Cross References

Resources	Reference
ChEBI	15640
ChEMBL	CHEMBL1679
DrugBank	DB00650
DrugCentral	1232
FDA SRS	Q573I9DVLP
Guide to Pharmacology	4816
PharmGKB	PA450198
PubChem	135403648
SureChEMBL	SCHEMBL8349

CONTENTS

Structure
Chemical and Physical Properties
Related Entries