S-3304


Synonyms	S 3304
Status
Molecule Category	UNKNOWN
UNII	BK459F050X
EPA CompTox	DTXSID20174292


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

Structure


InChI Key	YWCLDDLVLSQGSZ-JOCHJYFZSA-N
Smiles	Cc1ccc(C#Cc2ccc(S(=O)(=O)N[C@H](Cc3c[nH]c4ccccc34)C(=O)O)s2)cc1
InChI	InChI=1S/C24H20N2O4S2/c1-16-6-8-17(9-7-16)10-11-19-12-13-23(31-19)32(29,30)26-22(24(27)28)14-18-15-25-21-5-3-2-4-20(18)21/h2-9,12-13,15,22,25-26H,14H2,1H3,(H,27,28)/t22-/m1/s1

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C24H20N2O4S2
Molecular Weight	464.57
AlogP	3.91
Hydrogen Bond Acceptor	4.0
Hydrogen Bond Donor	3.0
Number of Rotational Bond	6.0
Polar Surface Area	99.26
Molecular species	ACID
Aromatic Rings	4.0
Heavy Atoms	32.0

Reference

Journal : J. Med. Chem.

Title : Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives.

PubMed ID : 9484512

DOI : 10.1021/jm9707582

Year : 1998

Volume : 41

Issue : 4

First Page : 640

Last Page : 649

Authors : Tamura Y, Watanabe F, Nakatani T, Yasui K, Fuji M, Komurasaki T, Tsuzuki H, Maekawa R, Yoshioka T, Kawada K, Sugita K, Ohtani M.

Abstract : Various N-sulfonylamino acid derivatives were synthesized and evaluated for their in vitro and in vivo activities to inhibit type IV collagenase (MMP-9 and MMP-2). When the amino acid residue and the sulfonamide moiety were modified, their inhibitory activities were greatly affected by the structure of the sulfonamide moiety. A series of aryl sulfonamide derivatives containing biaryl, tetrazole, amide, and triple bond were found to be potent and highly selective inhibitors of MMP-9 and MMP-2. In addition, these compounds were orally active in animal models of tumor growth and metastasis. These results revealed the potential of the N-sulfonylamino acid derivatives as a new type of candidate drug for the treatment of cancer.

Reference

Journal : J. Med. Chem.

Title : Homology modeling of gelatinase catalytic domains and docking simulations of novel sulfonamide inhibitors.

PubMed ID : 10346925

DOI : 10.1021/jm980514x

Year : 1999

Volume : 42

Issue : 10

First Page : 1723

Last Page : 1738

Authors : Kiyama R, Tamura Y, Watanabe F, Tsuzuki H, Ohtani M, Yodo M.

Abstract : Three-dimensional models for the catalytic domain of gelatinases (MMP-9 and -2) have been constructed based on the X-ray crystal structure of MMP-3. Conformations of the loop segment which forms the bottom half of the S1' subsite but shows conformational diversity among the crystal structures of other MMPs have been explored by simulated annealing of each gelatinase model complexed with two highly potent "probe" inhibitors. Representative catalytic domain models have been selected for each gelatinase from the set of generated conformations based on shape complementarity of the loop to the probe inhibitors. The single model selected for MMP-9 was utilized to explain the structure-activity relationship of our novel sulfonamide inhibitors. Molecular dynamics (MD) simulations of the complex models revealed important features of the binding mechanism of our inhibitors: (i) the ligand carboxylate group coordinating to the catalytic zinc ion and hydrogen bonding to the Glu219 side chain, (ii) one of the sulfonyl oxygens forming hydrogen bonds with the main chain NHs (Leu181 and Ala182), (iii) the sulfonyl substituent making extensive hydrophobic contact with the S1' subsite. The gauche conformation exclusively adopted by the sulfonamide C-N-S-C torsion plays an important role in achieving the third binding feature by properly directing the substituent into the S1' subsite. Improvement of the inhibitory activity according to straight elongation of the sulfonyl substituent was attributed to an increase of the hydrophobic contact between the substituent and the S1' subsite. Structural modifications which alter the straight shape of the substituent lead to deterioration of the activity. On the other hand, the two candidate models selected for MMP-2 differ in the bottom shape of the S1' subsite: one with a channel-like subsite and the other with a pocket-like subsite resembling that of the MMP-9 model. The bottom shape was experimentally probed by chemical synthesis of inhibitors having elongated sulfonyl substituents whose terminal alkyl groups were shown by MD simulations to protrude from the S1' subsite bottom into the solvent. Gelatinase assays of these inhibitors showed that elongation of the substituent significantly reduces activity against MMP-9 while retaining activity against MMP-2, consequently increasing the selectivity between MMP-2 and -9. The results confirm that MMP-9 has a pocket-like S1' subsite with a floorboard and MMP-2 has a channel-like S1' subsite.

Reference

Journal : J. Med. Chem.

Title : Highly selective and orally active inhibitors of type IV collagenase (MMP-9 and MMP-2): N-sulfonylamino acid derivatives.

PubMed ID : 9484512

DOI : 10.1021/jm9707582

Year : 1998

Volume : 41

Issue : 4

First Page : 640

Last Page : 649

Authors : Tamura Y, Watanabe F, Nakatani T, Yasui K, Fuji M, Komurasaki T, Tsuzuki H, Maekawa R, Yoshioka T, Kawada K, Sugita K, Ohtani M.

Reference

Journal : J. Med. Chem.

Title : Homology modeling of gelatinase catalytic domains and docking simulations of novel sulfonamide inhibitors.

PubMed ID : 10346925

DOI : 10.1021/jm980514x

Year : 1999

Volume : 42

Issue : 10

First Page : 1723

Last Page : 1738

Authors : Kiyama R, Tamura Y, Watanabe F, Tsuzuki H, Ohtani M, Yodo M.

Assay Description	Organism	Bioactivity
Inhibitory activity against human gelatinase A (matrix metalloprotease-2 MMP2)	None	20.0 nM
Inhibitory activity against Matrix metalloprotease-2 (concentration required for 50% inhibition of enzyme activity)	None	1.7 nM
Inhibitory activity against human gelatinase B (Matrix metalloprotease-9)	None	23.0 nM
Inhibitory activity against Matrix metalloprotease-9 (concentration required for 50% inhibition of enzyme activity)	None	9.6 nM

Cross References

Resources	Reference
ChEMBL	CHEMBL297792
DrugBank	DB12149
FDA SRS	BK459F050X
PubChem	10718956
SureChEMBL	SCHEMBL2380826

CONTENTS

Structure
Chemical and Physical Properties