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

ID: ALA192632

PubChem CID: 135800109

Max Phase: Preclinical

Molecular Formula: C21H23N5O6

Molecular Weight: 441.44

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  Nc1nc2[nH]c(CCCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cc2c(=O)[nH]1

Standard InChI:  InChI=1S/C21H23N5O6/c22-21-25-17-14(19(30)26-21)10-13(23-17)3-1-2-11-4-6-12(7-5-11)18(29)24-15(20(31)32)8-9-16(27)28/h4-7,10,15H,1-3,8-9H2,(H,24,29)(H,27,28)(H,31,32)(H4,22,23,25,26,30)/t15-/m0/s1

Standard InChI Key:  QLSVPQAGJDLITE-HNNXBMFYSA-N

Molfile:  

     RDKit          2D

 32 34  0  0  0  0  0  0  0  0999 V2000
   13.5656   -0.3584    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.2852   -0.7575    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.9925   -0.3355    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.9787    0.4903    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.2516    0.8922    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.5473    0.4638    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.6859    0.9181    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.4085    0.5169    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   15.6706    1.7429    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   17.1157    0.9447    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.8383    0.5434    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.1004    1.7695    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.8035    2.1932    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   16.3779    2.1666    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   17.8536   -0.2815    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.5721   -0.6786    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.5875   -1.5034    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   19.2794   -0.2549    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    8.5551    1.2643    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    8.1571    0.5422    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.5797   -0.1608    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    9.3799    1.2834    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.8027    0.5731    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.3999   -0.1498    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.9646   -0.7510    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   10.7137   -0.4038    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.6135    0.4161    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.7821    2.0054    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    7.3322    0.5268    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   11.4358   -0.8019    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.1435   -0.3791    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.8615   -0.7772    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
 15 16  1  0
  7  8  1  0
 16 17  2  0
 16 18  1  0
 19 20  1  0
  7  9  2  0
  4  5  1  0
  8 10  1  0
  2  3  1  0
 19 22  1  0
 20 21  2  0
 21 24  1  0
 23 22  1  0
 23 24  2  0
 10 11  1  0
  5  6  2  0
 10 12  1  6
  6  1  1  0
 12 13  2  0
 24 25  1  0
 25 26  1  0
 26 27  2  0
 27 23  1  0
  1  2  2  0
 22 28  2  0
 12 14  1  0
 20 29  1  0
  4  7  1  0
 26 30  1  0
 11 15  1  0
 30 31  1  0
  3  4  2  0
 31 32  1  0
 32  1  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA192632

   ---

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: 441.44

Molecular Weight (Monoisotopic): 441.1648

AlogP: 1.06

#Rotatable Bonds: 10

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: 4.84

CX LogP: 0.06

CX LogD: -5.09

Aromatic Rings: 3

Heavy Atoms: 32

QED Weighted: 0.27

Np Likeness Score: 0.07

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 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]

4. 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]

5. 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]

6. Xiang W, Dekhne A, Doshi A, O'Connor C, Hou Z, Matherly LH, Gangjee A..  (2019)  Discovery of amide-bridged pyrrolo[2,3-d]pyrimidines as tumor targeted classical antifolates with selective uptake by folate receptor α and inhibition of de novo purine nucleotide biosynthesis.,  27  (23): [PMID:31679978] [10.1016/j.bmc.2019.115125]

7. Golani LK, Wallace-Povirk A, Deis SM, Wong J, Ke J, Gu X, Raghavan S, Wilson MR, Li X, Polin L, de Waal PW, White K, Kushner J, O'Connor C, Hou Z, Xu HE, Melcher K, Dann CE, Matherly LH, Gangjee A..  (2016)  Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.,  59  (17): [PMID:27458733] [10.1021/acs.jmedchem.6b00594]

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