BATABULIN


Synonyms	Batabulin T-138067 T-67 T138067 T67 TL 057 TL-057
Status
Molecule Category	UNKNOWN
UNII	T4NP8G3K6Q
EPA CompTox	DTXSID70173230


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

Structure


InChI Key	ROZCIVXTLACYNY-UHFFFAOYSA-N
Smiles	COc1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1F
InChI	InChI=1S/C13H7F6NO3S/c1-23-7-3-2-5(4-6(7)14)20-24(21,22)13-11(18)9(16)8(15)10(17)12(13)19/h2-4,20H,1H3

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C13H7F6NO3S
Molecular Weight	371.26
AlogP	3.33
Hydrogen Bond Acceptor	3.0
Hydrogen Bond Donor	1.0
Number of Rotational Bond	4.0
Polar Surface Area	55.4
Molecular species	ACID
Aromatic Rings	2.0
Heavy Atoms	24.0

Reference

Journal : J. Med. Chem.

Title : Discovery of substituted N-phenyl nicotinamides as potent inducers of apoptosis using a cell- and caspase-based high throughput screening assay.

PubMed ID : 12773051

DOI : 10.1021/jm0205200

Year : 2003

Volume : 46

Issue : 12

First Page : 2474

Last Page : 2481

Authors : Cai SX, Nguyen B, Jia S, Herich J, Guastella J, Reddy S, Tseng B, Drewe J, Kasibhatla S.

Abstract : By applying a novel cell- and caspase-based HTS assay, a series of N-phenyl nicotinamides has been identified as a new class of potent inducers of apoptosis. Through SAR studies, a 20-fold increase in potency was achieved from a screening hit N-(4-methoxy-2-nitrophenyl)pyridine-3-carboxamide (1) to lead compound 6-methyl-N-(4-ethoxy-2-nitrophenyl)pyridine-3-carboxamide (10), with an EC(50) of 0.082 microM in the caspase activation assay in T47D breast cancer cells. The N-phenyl nicotinamides also were found to be active in the growth inhibition assay where compound 10 had a GI(50) value of 0.21 microM in T47D cells. More importantly, compound 10 was found to be equipotent in MES-SA cells and paclitaxel-resistant, p-glycoprotein overexpressed MES-SA/DX5 cells. Compounds 1 and 6-chloro-N-(4-ethoxy-2-nitrophenyl)pyridine-3-carboxamide (8), a more potent analogue, were found to arrest T47D cells in G(2)/M phase of the cell cycle followed by induction of apoptosis as measured by flow cytometry. Compound 8, which was more potent than 1 in the caspase activation assay, also was found to be more potent in G(2)/M arrest and apoptosis assay. These data confirm that the cell-based caspase activation assay is useful for screening for inducers of apoptosis, as well as for SAR studies and lead optimization. Upon further characterization, N-phenyl nicotinamides were found to be inhibitors of microtubule polymerization in vitro. The identification of N-phenyl nicotinamides as a novel series of inducers of apoptosis demonstrates that our cell- and caspase-based HTS assay is useful for the discovery and optimization of potentially novel anticancer agents.

Reference

Journal : J. Med. Chem.

Title : Discovery of substituted N-phenyl nicotinamides as potent inducers of apoptosis using a cell- and caspase-based high throughput screening assay.

PubMed ID : 12773051

DOI : 10.1021/jm0205200

Year : 2003

Volume : 46

Issue : 12

First Page : 2474

Last Page : 2481

Authors : Cai SX, Nguyen B, Jia S, Herich J, Guastella J, Reddy S, Tseng B, Drewe J, Kasibhatla S.

Reference

Journal : J. Med. Chem.

Title : Discovery of substituted N-phenyl nicotinamides as potent inducers of apoptosis using a cell- and caspase-based high throughput screening assay.

PubMed ID : 12773051

DOI : 10.1021/jm0205200

Year : 2003

Volume : 46

Issue : 12

First Page : 2474

Last Page : 2481

Authors : Cai SX, Nguyen B, Jia S, Herich J, Guastella J, Reddy S, Tseng B, Drewe J, Kasibhatla S.

Reference

Journal : J. Med. Chem.

Title : Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier.

PubMed ID : 11606124

DOI : 10.1021/jm000478d

Year : 2001

Volume : 44

Issue : 22

First Page : 3599

Last Page : 3605

Authors : Rubenstein SM, Baichwal V, Beckmann H, Clark DL, Frankmoelle W, Roche D, Santha E, Schwender S, Thoolen M, Ye Q, Jaen JC.

Abstract : The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization. Amides 3-6 were synthesized using standard methodologies and determined to be significantly less lipophilic than T138067 based on logP calculations. Tubulin polymerization and [(3)H]-T138067 competition assays revealed that these amides are pro-drugs for parent aniline 2. Amides 3-5 showed no detectable signs of crossing the blood brain barrier, while amide 6 was found in extremely small amounts (12 ng/g of brain tissue). Aniline 2, which was formed in vivo from these amides, was found in significantly smaller amounts (approximately 20 to >5000 times) in the brain than when 2 was administered directly. The in vivo efficacy of amide 6 approached that of T138067 and was better tolerated when administered to athymic nude mice bearing MX-1 human mammary tumor xenografts.

Reference

Journal : J. Med. Chem.

Title : Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier.

PubMed ID : 11606124

DOI : 10.1021/jm000478d

Year : 2001

Volume : 44

Issue : 22

First Page : 3599

Last Page : 3605

Authors : Rubenstein SM, Baichwal V, Beckmann H, Clark DL, Frankmoelle W, Roche D, Santha E, Schwender S, Thoolen M, Ye Q, Jaen JC.

Reference

Journal : J. Med. Chem.

Title : Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier.

PubMed ID : 11606124

DOI : 10.1021/jm000478d

Year : 2001

Volume : 44

Issue : 22

First Page : 3599

Last Page : 3605

Authors : Rubenstein SM, Baichwal V, Beckmann H, Clark DL, Frankmoelle W, Roche D, Santha E, Schwender S, Thoolen M, Ye Q, Jaen JC.

Reference

Journal : Eur J Med Chem

Title : Enediynes bearing polyfluoroaryl sulfoxide as new antiproliferative agents with dual targeting of microtubules and DNA.

PubMed ID : 29471119

DOI : 10.1016/j.ejmech.2018.02.030

Year : 2018

Volume : 148

First Page : 306

Last Page : 313

Authors : Borie C, Mondal S, Arif T, Briand M, Lingua H, Dumur F, Gigmes D, Stocker P, Barbarat B, Robert V, Nicoletti C, Olive D, Maresca M, Nechab M.

Abstract : A novel series of enediynes possessing pentafluorophenylsulfoxide have been developed. The innovative compounds possess antiproliferative activity against a broad panel of human cancer cells originating from breast, blood, lung, kidney, colon, prostate, pancreas or skin with IC50 ranging from 0.6 to 3.4 μM. The antiproliferative activity of enediynes in darkness is associated to their ability to compromise microtubule network. In addition, exposure to UV leads to double-stranded DNA cleavage caused by the newly synthesized molecules reducing further their IC50 in nanomolar range against human tumor cells, including chemo-resistant pancreatic cancer cells. Taken together, the examined data demonstrate that enediynes possessing pentafluorosulfoxide are promising molecules in the cancer therapy.

Assay Description	Organism	Bioactivity
Tested for caspase activation activity in colorectal DLD-1 cell line	Homo sapiens	150.0 nM
Tested for caspase activation activity in human breast cancer T47D cells	Homo sapiens	170.0 nM
Tested for caspase activation activity in human breast cancer ZR-75-1 cells	Homo sapiens	130.0 nM
Inhibition of growth of human cervical carcinoma (HeLa) cell line.	Homo sapiens	101.0 nM
Inhibition of growth of human mammary carcinoma (MCF-7) cell line.	Homo sapiens	46.0 nM
Inhibition of growth of human mammary carcinoma (MCF-7) cell line that exhibits the MDR phenotype.	Homo sapiens	87.0 nM
Antiproliferative activity against human HBL100 cells after 70 hrs by alamar blue assay	Homo sapiens	200.0 nM

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Cross References

Resources	Reference
ChEMBL	CHEMBL79280
DrugBank	DB16103
FDA SRS	T4NP8G3K6Q
PDB	T13
PubChem	216324
SureChEMBL	SCHEMBL18845

CONTENTS

Structure
Chemical and Physical Properties
Related Entries