Discovery, Synthesis, Pharmacological Profiling, and Biological Characterization of Brintonamides A-E, Novel Dual Protease and GPCR Modulators from a Marine Cyanobacterium

Journal of Medicinal Chemistry
Fatma H Al-AwadhiHendrik Luesch

Abstract

Five novel modified linear peptides named brintonamides A-E (1-5) were discovered from a marine cyanobacterial sample collected from Brinton Channel, Florida Keys. The total synthesis of 1-5 in addition to two other structurally related analogues (6 and 7) was achieved, which provided more material to allow rigorous biological evaluation and SAR studies. Compounds were subjected to cancer-focused phenotypic cell viability and migration assays and orthogonal target-based pharmacological screening platforms to identify their protease and GPCR modulatory activity profiles. The cancer related serine protease kallikrein 7 (KLK7) was inhibited to similar extents with an IC50 near 20 μM by both representative members 1 and 4, which differed in the presence or lack of the N-terminal unit. In contrast to the biochemical protease profiling study, clear SAR was observed in the functional GPCR screens, where five GPCRs in antagonist mode (CCR10, OXTR, SSTR3, TACR2) and agonist mode (CXCR7) were modulated by compounds 1-7 to varying extents. Chemokine receptor type 10 (CCR10) was potently modulated by brintonamide D (4) with an IC50 of 0.44 μM. We performed in silico modeling to understand the structural basis underlying the differences in ...Continue Reading

References

Jan 1, 1991·Archives of Dermatological Research·T Egelrud, A Lundström
Jul 2, 2004·Nature Reviews. Cancer·Fran Balkwill
Nov 2, 2004·Nature Reviews. Cancer·Carla A Borgoño, Eleftherios P Diamandis
Nov 3, 2004·Journal of Dermatological Science·Takashi MurakamiSam T Hwang
Dec 3, 2004·Cancer Research·Matthew C P SmithGary D Luker
May 25, 2005·Cancer Letters·Christina V Obiezu, Eleftherios P Diamandis
Aug 24, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Neslihan CabiogluAysegul Sahin
Apr 29, 2006·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Oriana SimonettiAnnamaria Offidani
Jun 30, 2006·Journal of Mammary Gland Biology and Neoplasia·Alessandra ReversiBice Chini
Aug 19, 2006·Clinical Chemistry·Shannon J C ShanEleftherios P Diamandis
Sep 11, 2007·Cancer Metastasis Reviews·Seema SinghRakesh K Singh
Sep 25, 2007·Clinical & Experimental Metastasis·Adit Ben-Baruch
Jun 28, 2008·Pigment Cell & Melanoma Research·Hwa Jin LeeSuzie Chen
Aug 9, 2008·Clinical Chemistry·Nashmil Emami, Eleftherios P Diamandis
Dec 15, 2010·Pathology, Research and Practice·Hiromichi KaiShinichi Sato
Jul 16, 2011·Clinical, Cosmetic and Investigational Dermatology·Henriette Farkas, Lilian Varga
Oct 18, 2011·Journal of Natural Products·Marcelino GutiérrezWilliam H Gerwick
May 11, 2012·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Vladimir IakovlevRandy S Haun
May 19, 2012·Nature Reviews. Drug Discovery·Guy Griebel, Florian Holsboer
Sep 11, 2012·Bioorganic & Medicinal Chemistry Letters·Renato F FreitasLuciano Puzer
Oct 24, 2012·Trends in Pharmacological Sciences·Georgia Sotiropoulou, Georgios Pampalakis
Nov 13, 2012·Chembiochem : a European Journal of Chemical Biology·Rana MontaserHendrik Luesch
Nov 22, 2013·Oncotarget·Purvaba J SarvaiyaMaciej S Lesniak
Apr 2, 2014·The Canadian Journal of Cardiology·Stephen S G Ferguson, Ross D Feldman
Jun 14, 2012·ACS Medicinal Chemistry Letters·Shuwen HeWilliam K Hagmann
Jun 6, 2014·ACS Medicinal Chemistry Letters·Jocelia P C OliveiraLuciano Puzer
May 26, 2015·ACS Medicinal Chemistry Letters·Shrenik K ShahWilliam K Hagmann

❮ Previous
Next ❯

Citations

Feb 7, 2020·Natural Product Reports·Anthony R CarrollMichèle R Prinsep
Feb 27, 2020·Pharmaceuticals·Nicole Lounsbury
Jul 29, 2019·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xiao LiangHendrik Luesch
Apr 6, 2021·World Journal of Biological Chemistry·Rama Rao MallaGanji Purnachandra Nagaraju
May 1, 2021·Journal of Industrial Microbiology & Biotechnology·Dipesh DhakalYousong Ding
Sep 21, 2018·Organic Letters·Jia-Lei YanTao Ye
Feb 13, 2020·Organic Letters·Mingze YangTao Ye
May 8, 2019·Organic Letters·Jie YuTao Ye
Jan 9, 2020·Journal of Medicinal Chemistry·Verrill M NorwoodRobert W Huigens
Feb 20, 2019·Organic Letters·Xiao LiangHendrik Luesch

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Migration in Cancer and Metastasis

Migration of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. Discover the latest research on cell migration in cancer and metastasis here.

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.