360796-40-3Relevant academic research and scientific papers
Efficient synthetic methodology for the construction of dihydronaphthalene and benzosuberene molecular frameworks
Mondal, Deboprosad,Niu, Haichan,Pinney, Kevin G.
, p. 397 - 401 (2019/01/05)
Benzosuberene analogues (1 and 2) and dihydronaphthalene analogues (3 and 4) function as potent inhibitors of tubulin polymerization, demonstrate pronounced cytotoxicity (low nM to pM range) against human cancer cell lines, and are promising vascular disrupting agents (VDAs). As such, these compounds represent lead anticancer agents with potential translatability towards the clinic. Methodology previously established by us (and others) facilitated synthetic access to a variety of structural and functional group modifications necessary to explore structure activity relationship considerations directed towards the development of these (and related) molecules as potential therapeutic agents. During the course of these studies it became apparent that the availability of synthetic methodology to facilitate direct conversion of the phenolic-based compounds to their corresponding aniline congeners would be beneficial. Accordingly, modified synthetic routes toward these target phenols (benzosuberene 1 and dihydronaphthalene 3) were developed in order to improve scalability and overall yield [45-57% (1) and 32% (3)]. Moreover, benzosuberene-based phenolic analogue 1 and separately dihydronaphthalene-based phenolic analogue 3 were successfully converted into their corresponding aniline analogues 2 and 4 in good yield (>60% over three steps) using a palladium catalyzed amination reaction.
Synthesis of dihydronaphthalene analogues inspired by combretastatin A-4 and their biological evaluation as anticancer agents
Maguire, Casey J.,Chen, Zhi,Mocharla, Vani P.,Sriram, Madhavi,Strecker, Tracy E.,Hamel, Ernest,Zhou, Heling,Lopez, Ramona,Wang, Yifan,Mason, Ralph P.,Chaplin, David J.,Trawick, Mary Lynn,Pinney, Kevin G.
, p. 1649 - 1662 (2018/10/26)
The natural products colchicine and combretastatin A-4 (CA4) have provided inspiration for the discovery and development of a wide array of derivatives and analogues that inhibit tubulin polymerization through a binding interaction at the colchicine site on β-tubulin. A water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) has demonstrated the ability to selectively damage tumor-associated vasculature and ushered in a new class of developmental anticancer agents known as vascular disrupting agents (VDAs). Through a long-term program of structure activity relationship (SAR) driven inquiry, we discovered that the dihydronaphthalene molecular scaffold provided access to small-molecule inhibitors of tubulin polymerization. In particular, a dihydronaphthalene analogue bearing a pendant trimethoxy aryl ring (referred to as KGP03) and a similar aroyl ring (referred to as KGP413) were potent inhibitors of tubulin polymerization (IC50 = 1.0 and 1.2 μM, respectively) and displayed low nM cytotoxicity against human cancer cell lines. In order to enhance water-solubility for in vivo evaluation, the corresponding phosphate prodrug salts (KGP04 and KGP152, respectively) were synthesized. In a preliminary in vivo study in a SCID-BALB/c mouse model bearing the human breast tumor MDA-MB-231-luc, a 99% reduction in signal was observed with bioluminescence imaging (BLI) 4 h after IP administration of KGP152 (200 mg kg?1) indicating reduced tumor blood flow. In a separate study, disruption of tumor-associated blood flow in a Fischer rat bearing an A549-luc human lung tumor was observed by color Doppler ultrasound following administration of KGP04 (15 mg kg?1).
Conformationnally restricted naphthalene derivatives type isocombretastatin A-4 and isoerianin analogues: Synthesis, cytotoxicity and antitubulin activity
Rasolofonjatovo, Evelia,Provot, Olivier,Hamze, Abdallah,Rodrigo, Jordi,Bignon, Jérome,Wdzieczak-Bakala, Joanna,Desravines, Déborah,Dubois, Jo?lle,Brion, Jean-Daniel,Alami, Mouad
, p. 22 - 32 (2012/07/27)
A novel series of dihydronaphtalene, tetrahydronaphtalene and naphtalene derivatives as restricted analogues of isoCA-4 were designed, synthesized and evaluated for their anticancer properties. High cell growth inhibition against four tumour cell lines was observed at a nanomolar level with dihydronaphtalenes 1d, e and 1h, tetrahydronaphtalene 2c and naphtalene 3c. Structure-activity relationships are also considered. These compounds exhibited a significant inhibitory activity toward tubulin polymerization (IC50 = 2-3 μM), comparable to that of isoCA-4. The effect of the lead compounds 1e and 2c on the cancer cells tested was associated with cell cycle arrest in the G 2/M phase. Docking studies reveal that these compounds showed a binding mode similar to those observed with their non-constraint isoCA-4 and isoerianin congeners.
