(S)-2-{4-[4-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)-butyl]-benzoylamino}-pentanedioic acid

ID: ALA365307

PubChem CID: 135567027

Max Phase: Preclinical

Molecular Formula: C22H25N5O6

Molecular Weight: 455.47

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  Nc1nc2[nH]c(CCCCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cc2c(=O)[nH]1

Standard InChI:  InChI=1S/C22H25N5O6/c23-22-26-18-15(20(31)27-22)11-14(24-18)4-2-1-3-12-5-7-13(8-6-12)19(30)25-16(21(32)33)9-10-17(28)29/h5-8,11,16H,1-4,9-10H2,(H,25,30)(H,28,29)(H,32,33)(H4,23,24,26,27,31)/t16-/m0/s1

Standard InChI Key:  CEPQCJFDTGQKDN-INIZCTEOSA-N

Molfile:  

     RDKit          2D

 33 35  0  0  0  0  0  0  0  0999 V2000
   -2.9746   -0.2704    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -2.9746   -1.1000    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.2600   -1.5125    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -2.2600    0.1466    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.5411   -0.2704    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.5365   -1.1010    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.7451   -1.3533    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -0.2606   -0.6787    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.7525   -0.0095    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.5644   -0.6741    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.9809   -1.3862    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.8058   -1.3817    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.2223   -2.0938    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.0473   -2.0892    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.2612    0.9716    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -3.6890   -1.5125    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    3.4605   -2.8004    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.2848   -2.7962    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.6942   -2.0790    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.2732   -1.3644    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.4504   -1.3721    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.5192   -2.0732    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.9365   -2.7848    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    5.9267   -1.3559    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    6.7615   -2.7791    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.1789   -3.4908    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.7713   -4.2081    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.1887   -4.9197    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.7812   -5.6370    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    8.0137   -4.9140    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    7.1690   -2.0619    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.9940   -2.0562    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    6.7517   -1.3502    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
  2 16  1  0
  6  7  1  0
 14 17  2  0
  7  8  1  0
 17 18  1  0
  8  9  2  0
 18 19  2  0
  9  5  1  0
 19 20  1  0
  5  4  1  0
 20 21  2  0
 21 14  1  0
  8 10  1  0
 19 22  1  0
  5  6  2  0
 22 23  1  0
 10 11  1  0
 22 24  2  0
 25 23  1  6
 11 12  1  0
 25 26  1  0
  1  2  1  0
 26 27  1  0
 12 13  1  0
 27 28  1  0
  1  4  1  0
 28 29  1  0
 13 14  1  0
 28 30  2  0
  2  3  2  0
 25 31  1  0
  4 15  2  0
 31 32  1  0
  3  6  1  0
 31 33  2  0
M  END

Alternative Forms

1. Parent:

   

   ALA365307

   ---

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

Calculated Properties

Molecular Weight: 455.47

Molecular Weight (Monoisotopic): 455.1805

AlogP: 1.45

#Rotatable Bonds: 11

Polar Surface Area: 191.26

Molecular Species: ACID

HBA: 6

HBD: 6

#RO5 Violations: 1

HBA (Lipinski): 11

HBD (Lipinski): 7

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 3.33

CX Basic pKa: 4.88

CX LogP: 0.50

CX LogD: -4.62

Aromatic Rings: 3

Heavy Atoms: 33

QED Weighted: 0.23

Np Likeness Score: 0.06

References

1. Gangjee A, Zeng Y, McGuire JJ, Kisliuk RL..  (2005)  Synthesis of classical, four-carbon bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates.,  48  (16): [PMID:16078850] [10.1021/jm058213s]

2. Deng Y, Wang Y, Cherian C, Hou Z, Buck SA, Matherly LH, Gangjee A..  (2008)  Synthesis and discovery of high affinity folate receptor-specific glycinamide ribonucleotide formyltransferase inhibitors with antitumor activity.,  51  (16): [PMID:18680275] [10.1021/jm8003366]

3. Wang L, Cherian C, Desmoulin SK, Polin L, Deng Y, Wu J, Hou Z, White K, Kushner J, Matherly LH, Gangjee A..  (2010)  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.,  53  (3): [PMID:20085328] [10.1021/jm9015729]

4. Wang Y, Cherian C, Orr S, Mitchell-Ryan S, Hou Z, Raghavan S, Matherly LH, Gangjee A..  (2013)  Tumor-targeting with novel non-benzoyl 6-substituted straight chain pyrrolo[2,3-d]pyrimidine antifolates via cellular uptake by folate receptor α and inhibition of de novo purine nucleotide biosynthesis.,  56  (21): [PMID:24111942] [10.1021/jm401139z]

5. Mitchell-Ryan S, Wang Y, Raghavan S, Ravindra MP, Hales E, Orr S, Cherian C, Hou Z, Matherly LH, Gangjee A..  (2013)  Discovery of 5-substituted pyrrolo[2,3-d]pyrimidine antifolates as dual-acting inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis: implications of inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase to ampk activation and antitumor activity.,  56  (24): [PMID:24256410] [10.1021/jm401328u]

6. Ravindra M, Wallace-Povirk A, Karim MA, Wilson MR, O'Connor C, White K, Kushner J, Polin L, George C, Hou Z, Matherly LH, Gangjee A..  (2018)  Tumor Targeting with Novel Pyridyl 6-Substituted Pyrrolo[2,3- d]Pyrimidine Antifolates via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of De Novo Purine Nucleotide Biosynthesis.,  61  (5): [PMID:29425443] [10.1021/acs.jmedchem.7b01708]

7. Ravindra M, Wilson MR, Tong N, O'Connor C, Karim M, Polin L, Wallace-Povirk A, White K, Kushner J, Hou Z, Matherly LH, Gangjee A..  (2018)  Fluorine-Substituted Pyrrolo[2,3- d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.,  61  (9): [PMID:29701475] [10.1021/acs.jmedchem.8b00408]

8. Golani LK, Islam F, O'Connor C, Dekhne AS, Hou Z, Matherly LH, Gangjee A..  (2020)  Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier.,  28  (12): [PMID:32503687] [10.1016/j.bmc.2020.115544]

9. Gangjee, A A and 5 more authors.  1994-04-15  Classical and nonclassical furo[2,3-d]pyrimidines as novel antifolates: synthesis and biological activities.  [PMID:8164259]

10. Tarnchompoo, Bongkoch B and 8 more authors.  2002-03-14  Development of 2,4-diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R+S108N mutants of dihydrofolate reductase from pyrimethamine-resistant Plasmodium falciparum.  [PMID:11881993]

11. Santos, M Amélia MA and 5 more authors.  2007-02-01  Methotrexate gamma-hydroxamate derivatives as potential dual target antitumor drugs.  [PMID:17127067]

12. Thurmond, John J and 17 more authors.  2008-02-14  Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy.  [PMID:18205293]

13. Gangjee, Aleem; Jain, Hiteshkumar D; Queener, Sherry F and Kisliuk, Roy L.  2008-08-14  The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents.  [PMID:18605720]

14. Gangjee, Aleem; Qiu, Yibin; Li, Wei and Kisliuk, Roy L.  2008-09-25  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.  [PMID:18800768]

15. Izbicka, E and 6 more authors.  2009-10  Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers.  [PMID:19221750]

16. Gangjee, Aleem and 6 more authors.  2009-08-13  Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents.  [PMID:19719239]

17. Gangjee, Aleem and 9 more authors.  2009-10-15  Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors.  [PMID:19748785]

18. Gangjee, Aleem and 5 more authors.  2010-01-15  2,4-Diamino-5-methyl-6-substituted arylthio-furo[2,3-d]pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors.  [PMID:20056546]

19. Gangjee, Aleem and 5 more authors.  2010-02-25  Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.  [PMID:20092323]

20. Zhang, Xin X and 5 more authors.  2011-06-01  Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.  [PMID:21550809]

21. Gangjee, Aleem A and 5 more authors.  2012-07-15  Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.  [PMID:22739090]

22. Gangjee, Aleem and 5 more authors.  2013-06-13  Design, synthesis, and molecular modeling of novel pyrido[2,3-d]pyrimidine analogues as antifolates; application of Buchwald-Hartwig aminations of heterocycles.  [PMID:23627352]

23. Cao, Sheng-Li SL and 10 more authors.  2013-06  Synthesis and antiproliferative activity of 4-substituted-piperazine-1-carbodithioate derivatives of 2,4-diaminoquinazoline.  [PMID:23665106]

24. Piras, Sandra S and 7 more authors.  2014-03-21  2-[N-Alkyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines as anticancer agents inhibitors of folate enzymes.  [PMID:24531230]

25. G-Dayanandan, Narendran and 11 more authors.  2014-03-27  Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata.  [PMID:24568657]

26. Chao, Bo; Li, Bingbing X and Xiao, Xiangshu.  2015-04-01  The chemistry and pharmacology of privileged pyrroloquinazolines.  [PMID:25937878]

27. Welsch, Matthew E ME and 9 more authors.  2016-12-08  Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design.  [PMID:27994750]

28. Gopalsamy, Ariamala A and 18 more authors.  2017-04-13  Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA).  [PMID:28257199]

29. Zaware, Nilesh N, Kisliuk, Roy R, Bastian, Anja A, Ihnat, Michael A MA and Gangjee, Aleem A.  2017-04-01  Synthesis and evaluation of 5-(arylthio)-9H-pyrimido[4,5-b]indole-2,4-diamines as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.  [PMID:28258797]

30. Tonelli, Michele M and 8 more authors.  2017-07-28  Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus.  [PMID:28477572]

31. Shah, Khushbu and 5 more authors.  2018-05-15  Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents.  [PMID:29691153]

32. Francesconi, Valeria V and 7 more authors.  2018-07-15  Synthesis, biological evaluation and molecular modeling of novel azaspiro dihydrotriazines as influenza virus inhibitors targeting the host factor dihydrofolate reductase (DHFR).  [PMID:29886325]

33. Hopper, Allen T and 8 more authors.  2019-02-14  Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis.  [PMID:30624926]

34. Sharma, Kalicharan K and 8 more authors.  2019-04-01  Expansion of a novel lead targeting M. tuberculosis DHFR as antitubercular agents.  [PMID:30827867]

Source

Source(1):

• Scientific Literature