ID: ALA422395

Max Phase: Preclinical

Molecular Formula: C24H23N5O6

Molecular Weight: 477.48

Molecule Type: Small molecule

Representations

Canonical SMILES:  C#CCN(Cc1ccc2[nH]c(N)nc(=O)c2c1)c1ccc(C(=O)NC(CCC(=O)O)C(=O)O)cc1

Standard InChI:  InChI=1S/C24H23N5O6/c1-2-11-29(13-14-3-8-18-17(12-14)22(33)28-24(25)27-18)16-6-4-15(5-7-16)21(32)26-19(23(34)35)9-10-20(30)31/h1,3-8,12,19H,9-11,13H2,(H,26,32)(H,30,31)(H,34,35)(H3,25,27,28,33)

Standard InChI Key:  LTKHPMDRMUCUEB-UHFFFAOYSA-N

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Small molecule

Topical: No

First In Class: No

Black Box: No

Chirality: No

Availability: No

Prodrug: No

Properties

Molecular Weight: 477.48

Molecular Weight (Monoisotopic): 477.1648

AlogP: 1.19

#Rotatable Bonds: 10

Polar Surface Area: 178.71

Molecular Species: ACID

HBA: 7

HBD: 5

#RO5 Violations: 0

HBA (Lipinski): 11

HBD (Lipinski): 6

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 3.24

CX Basic pKa: 3.54

CX LogP: 1.15

CX LogD: -4.72

Aromatic Rings: 3

Heavy Atoms: 35

QED Weighted: 0.27

Np Likeness Score: -0.62

References

1. Jones TR, Smithers MJ, Betteridge RF, Taylor MA, Jackman AL, Calvert AH, Davies LC, Harrap KR..  (1986)  Quinazoline antifolates inhibiting thymidylate synthase: variation of the amino acid.,  29  (6): [PMID:3712376] [10.1021/jm00156a033]

2. Caperelli CA..  (1987)  N10-substituted 5,8-dideazafolate inhibitors of glycinamide ribonucleotide transformylase.,  30  (7): [PMID:3599031] [10.1021/jm00390a024]

3. Nair MG, Dhawan R, Ghazala M, Kalman TI, Ferone R, Gaumont Y, Kisliuk RL..  (1987)  Folate analogues. 30. Synthesis and biological evaluation of N10-propargyl-5,8-dideaza-5,6,7,8-tetrahydrofolic acid and related compounds.,  30  (7): [PMID:3599032] [10.1021/jm00390a025]

4. Ghazala M, Nair MG, Toghiyani TR, Kisliuk RL, Gaumont Y, Kalman TI..  (1986)  Folate analogues. 25. Synthesis and biological evaluation of N10-propargylfolic acid and its reduced derivatives.,  29  (7): [PMID:3100797] [10.1021/jm00157a600]

5. Patil SD, Jones C, Nair MG, Galivan J, Maley F, Kisliuk RL, Gaumont Y, Duch D, Ferone R..  (1989)  Folate analogues. 32. Synthesis and biological evaluation of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid and related compounds.,  32  (6): [PMID:2542557] [10.1021/jm00126a023]

6. Jones TR, Calvert AH, Jackman AL, Eakin MA, Smithers MJ, Betteridge RF, Newell DR, Hayter AJ, Stocker A, Harland SJ..  (1985)  Quinazoline antifolates inhibiting thymidylate synthase: variation of the N10 substituent.,  28  (10): [PMID:4045922] [10.1021/jm00148a016]

7. Appelt K, Bacquet RJ, Bartlett CA, Booth CL, Freer ST, Fuhry MA, Gehring MR, Herrmann SM, Howland EF, Janson CA..  (1991)  Design of enzyme inhibitors using iterative protein crystallographic analysis.,  34  (7): [PMID:2066965] [10.1021/jm00111a001]

8. McNamara DJ, Berman EM, Fry DW, Werbel LM..  (1990)  Potent inhibition of thymidylate synthase by two series of nonclassical quinazolines.,  33  (7): [PMID:2362285] [10.1021/jm00169a040]

9. Costi PM, Rinaldi M, Tondi D, Pecorari P, Barlocco D, Ghelli S, Stroud RM, Santi DV, Stout TJ, Musiu C, Marangiu EM, Pani A, Congiu D, Loi GA, La Colla P..  (1999)  Phthalein derivatives as a new tool for selectivity in thymidylate synthase inhibition.,  42  (12): [PMID:10377217] [10.1021/jm9900016]

10. Li SW, Nair MG, Edwards DM, Kisliuk RL, Gaumont Y, Dev IK, Duch DS, Humphreys J, Smith GK, Ferone R..  (1991)  Folate analogues. 35. Synthesis and biological evaluation of 1-deaza, 3-deaza, and bridge-elongated analogues of N10-propargyl-5,8-dideazafolic acid.,  34  (9): [PMID:1895294] [10.1021/jm00113a011]

11. Bavetsias V, Marriott JH, Theti DS, Melin JC, Wilson SC, Jackman AL..  (2001)  Cyclopenta[g]quinazoline-based antifolates: the effect of the chirality at the 6-position on the inhibition of thymidylate synthase (TS).,  11  (23): [PMID:11714600] [10.1016/s0960-894x(01)00612-6]

12. Gangjee A, Zeng Y, McGuire JJ, Kisliuk RL..  (2000)  Effect of C9-methyl substitution and C8-C9 conformational restriction on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines.,  43  (16): [PMID:10956221] [10.1021/jm000130i]

13. Piper JR, Malik ND, Rhee MS, Galivan J, Sirotnak FM..  (1992)  Synthesis and antifolate evaluation of the 10-propargyl derivatives of 5-deazafolic acid, 5-deazaaminopterin, and 5-methyl-5-deazaaminopterin.,  35  (2): [PMID:1732551] [10.1021/jm00080a019]

14. Gangjee A, Devraj R, McGuire JJ, Kisliuk RL..  (1995)  5-Arylthio-substituted 2-amino-4-oxo-6-methylpyrrolo[2,3-d]pyrimidine antifolates as thymidylate synthase inhibitors and antitumor agents.,  38  (22): [PMID:7473577] [10.1021/jm00022a015]

15. Hynes JB, Patil SA, Tomazic A, Kumar A, Pathak A, Tan XH, Li XQ, Ratnam M, Delcamp TJ, Freisheim JH..  (1988)  Inhibition of murine thymidylate synthase and human dihydrofolate reductase by 5,8-dideaza analogues of folic acid and aminopterin.,  31  (2): [PMID:3339615] [10.1021/jm00397a031]

16. Jones TR, Smithers MJ, Taylor MA, Jackman AL, Calvert AH, Harland SJ, Harrap KR..  (1986)  Quinazoline antifolates inhibiting thymidylate synthase: benzoyl ring modifications.,  29  (4): [PMID:3754284] [10.1021/jm00154a007]

17. Berman EM, Werbel LM..  (1991)  The renewed potential for folate antagonists in contemporary cancer chemotherapy.,  34  (2): [PMID:1995868] [10.1021/jm00106a001]

18. Marsham PR, Chambers P, Hayter AJ, Hughes LR, Jackman AL, O'Connor BM, Bishop JA, Calvert AH..  (1989)  Quinazoline antifolate thymidylate synthase inhibitors: nitrogen, oxygen, sulfur, and chlorine substituents in the C2 position.,  32  (3): [PMID:2918503] [10.1021/jm00123a010]

19. Nair MG, Salter DC, Kisliuk RL, Gaumont Y, North G, Sirotnak FM..  (1983)  Folate analogues. 21. Synthesis and antifolate and antitumor activities of N10-(cyanomethyl)-5,8-dideazafolic acid.,  26  (4): [PMID:6403710] [10.1021/jm00358a030]

20. Jones TR, Thornton TJ, Flinn A, Jackman AL, Newell DR, Calvert AH..  (1989)  Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency.,  32  (4): [PMID:2704030] [10.1021/jm00124a018]

21. Hynes JB, Patil SA, Hagan RL, Cole A, Kohler W, Freisheim JH..  (1989)  Comparison of the biological effects of selected 5,8-dideazafolate analogues with their 2-desamino counterparts.,  32  (4): [PMID:2704031] [10.1021/jm00124a019]

22. Jones TR, Varney MD, Webber SE, Lewis KK, Marzoni GP, Palmer CL, Kathardekar V, Welsh KM, Webber S, Matthews DA, Appelt K, Smith WW, Janson CA, Villafranca JE, Bacquet RJ, Howland EF, Booth CL, Herrmann SM, Ward RW, White J, Moomaw EW, Bartlett CA, Morse CA..  (1996)  Structure-based design of lipophilic quinazoline inhibitors of thymidylate synthase.,  39  (4): [PMID:8632414] [10.1021/jm9502652]

23. Gangjee A, Lin X, Kisliuk RL, McGuire JJ..  (2005)  Synthesis of N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid as dual inhibitors of dihydrofolate reductase and thymidylate synthase and as potential antitumor agents.,  48  (23): [PMID:16279780] [10.1021/jm058234m]

24. Gangjee A, Qiu Y, Li W, Kisliuk RL..  (2008)  Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine antifolates.,  51  (18): [PMID:18800768] [10.1021/jm8006933]

25. PubChem BioAssay data set, 

26. Gangjee A, Zhao Y, Ihnat MA, Thorpe JE, Bailey-Downs LC, Kisliuk RL..  (2012)  Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.,  20  (14): [PMID:22739090] [10.1016/j.bmc.2012.05.068]

27.  (2016)  Tricyclic compounds having cytostatic and/or cytotoxic activity and methods of use thereof, 

Source

Source(3):

• Scientific Literature
• PubChem BioAssays
• BindingDB Database