New Drug Approvals

Home » Uncategorized » Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600E Inhibitor

Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600E Inhibitor

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

PAYPAL DONATIONS

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Blog Stats

  • 1,309,844 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,782 other followers

add to any

Share

Abstract Image

str1

N-(5-amino-2-tert-butyl)-11-fluorbenzol[f]thiazol-[4,5-h]-quinazolin-10-yl)-2,6-difluorbenzolsulfonamide = Dabrafenib_photo (2)

C23H18F3N5O2S2 (Mr = 517.09)

Solution of 5 mg (9.6 μmol) dabrafenib in 2 ml THF was irradiated at 365 nm with 5.4 W for 2 min. This procedure was repeated 18 times at room temperature. The reaction batches were combined. The total initial weight of dabrafenib was 101 mg (190 μmol). The solvent was removed under reduced pressure and the residue was purified by the flash chromatography (SiO2 reversed phase, MeOH/water gradient 50:50 to 100:0) to give compound 2 as a yellowish solid (36.2 mg, 70.0 μmol, yield: 37%).

1H-NMR (DMSO-d6 , 300 MHz): δ = 1.52 (s, 9 H, H-8), 7.28 (m, 2 H, NH2), 7.28 (ddd, 5 J = 0.4 Hz, 4 J = 1.7 Hz, 3 J = 8.5 Hz, 3 J = 8.9 Hz, 2 H, H-18), 7.59 (dd, 3 J = 7.4 Hz, 3 J = 7.8 Hz, 1 H, H-13), 7.71 (tt, 4 J = 6.1 Hz, 3 J = 8.5 Hz, 1 H, H-19), 8.56 (dd, 4 J = 0.9 Hz, 3 J = 9.3 Hz, 1 H, H-14), 9.79 (s, 1 H, H-2), 11.01 (s, 1 H, NH) ppm.

13C-NMR (DMSO-d6 , 300 MHz): δ = 30.4 (s, C-8), 38.3 (s, C-7), 110.9 (d, 4 JCF = 1.6 Hz, C-3), 113.4 (dd, 2 JCF = 22.7 Hz, 2 JCH = 3.5 Hz, C-18), 114.6 (d, 3 JCF = 10.3 Hz, C-9), 117.4 (d, 2 JCF = 16.1 Hz, C-16), 117.6 (dd, 4 JCF = 0.54 Hz, 2 JCH = 4.4 Hz, C-13), 120.8 (d, 2 JCF = 12.3 Hz, C-10), 125.4 (s, C-13), 129.3 (d, 3 JCF = 3.9 Hz, C-15), 130.6 (s, C-5), 135.9 (tt, 3 JCF = 10.9 Hz, 2 JCH = 3.3 Hz, C-19), 148.8 (dd, 2 JCF = 0.54 Hz, 2 JCH = 7.2 Hz, C-12), 149.2 (s, C-4), 150.1 (s, C-11), 157.1 160.5 (dd, 3 JFF = 257.3 Hz, 2 JCF = 3.61 Hz, C-4), 157.9 (s, C-2), 162.1 (s, C-1), 184.0 (s, C-6) ppm.

15N-HMBC (DMSO-d6 , 300 MHz): δ = 9.79/-119.60, 11.01/-268.37 ppm. 19F-NMR (DMSO-d6 , 300 MHz): δ = -121.03 (s, 1 F, F-11), -107.18 (m, 2 F, F-17) ppm.

HRMS (EI, 205 °C, THF): m/z = 517.0849 [M]+ .

LC-MS (ESI, 70 eV, MeOH): tR = 9.3 min; m/z (%) = 518.1 (100) [M+H]+

IR (ATR):  ̃ = 3490 (N-H), 3176 (arom. C-H), 2926 (C-H3), 1696 (N=N), 1613 (N-H), 1587, 1522, 1488, 1469 (arom. C=C), 1342 (sulfonamide), 1277, 1240, 1174 (C-F) cm-1 .

Photoinduced Conversion of Antimelanoma Agent Dabrafenib to a Novel Fluorescent BRAFV600E Inhibitor

Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00340
Publication Date (Web): September 20, 2016
Copyright © 2016 American Chemical Society
*E-mail: cpeifer@pharmazie.uni-kiel.de. Tel: +49-431-880-1137.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract

Dabrafenib (Tafinlar) was approved in 2013 by the FDA as a selective single agent treatment for patients with BRAFV600E mutation-positive advanced melanoma. One year later, a combination of dabrafenib and trametinib was used for treatment of BRAFV600E/K mutant metastatic melanoma. In the present study, we report on hitherto not described photosensitivity of dabrafenib both in organic and aqueous media. The half-lives for dabrafenib degradation were determined. Moreover, we revealed photoinduced chemical conversion of dabrafenib to its planar fluorescent derivative dabrafenib_photo 2. This novel compound could be isolated and biologically characterized in vitro. Both enzymatic and cellular assays proved that 2 is still a potent BRAFV600E inhibitor. The intracellular formation of 2 from dabrafenib upon ultraviolet irradiation is shown. The herein presented findings should be taken in account when handling dabrafenib both in preclinical research and in clinical applications.

////////Photoinduced Conversion, Antimelanoma Agent,  Dabrafenib, Novel Fluorescent BRAFV600E Inhibitor, BRAFV600E; Dabrafenib, fluorescent probe kinase inhibitor photoinduced conversion


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Paypal Donate

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,782 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

View Full Profile →

TWITTER

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: