803712-71-2

Upstream product

• 69778-83-2 4-methoxy-3-pyrrolin-2-one 
• 617-84-5 N-formyldiethylamine 
• 85153-60-2 C₆H₉ClO₃ 

Downstream Products

• 803712-70-1 tert-butyl 2-(5-formyl-4-methoxy-1H-pyrrol-2-yl)-1H-indole-1-carboxylate 
• 10476-41-2 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde 
• 60658-98-2 3-methoxy-5-phenyl-1H-pyrrole-2-carbaldehyde 
• 1033391-26-2 tert-butyl 2-(5-formyl-4-methoxy-1H-pyrrol-2-yl)-1H-indole-1-carboxylate 
• 896138-55-9 2-((3-methoxy-5-phenyl-2H-pyrrol-2-ylidene)methyl)-3,5-dimethyl-1H-pyrrole 
• 803712-67-6 obatoclax 

Relevant academic research and scientific papers

Total Synthesis and Antimalarial Activity of 2-(p-Hydroxybenzyl)-prodigiosins, Isoheptylprodigiosin, and Geometric Isomers of Tambjamine MYP1 Isolated from Marine Bacteria

Highly efficient and straightforward synthetic routes toward the first total synthesis of 2-(p-hydroxybenzyl)-prodigiosins (2-5), isoheptylprodigiosin (6), and geometric isomers of tambjamine MYP1 ((E/Z)-7) have been developed. The crucial steps involved in these synthetic routes are the construction of methoxy-bipyrrole-carboxaldehydes (MBCs) and a 20-membered macrocyclic core and a regioselective demethylation of MBC analogues. These new synthetic routes enabled us to generate several natural prodiginines24-27in larger quantity. All of the synthesized natural products exhibited potent asexual blood-stage antiplasmodial activity at low nanomolar concentrations against a panel ofPlasmodium falciparumparasites, with a great therapeutic index. Notably, prodiginines6and24-27provided curative in vivo efficacy against erythrocyticPlasmodium yoeliiat 25 mg/kg × 4 days via oral route in a murine model. No overt clinical toxicity or behavioral change was observed in any mice treated with prodiginines and tambjamines.

Mitochondrial Impairment by Cyanine-Based Small Molecules Induces Apoptosis in Cancer Cells

Mitochondrion, the powerhouse of the cells, has emerged as one of the unorthodox targets in anticancer therapy due to its involvement in several cellular functions. However, the development of small molecules for selective mitochondrial damage in cancer c

Novel imidazopyridine suppresses STAT3 activation by targeting SHP-1

The unregulated activation of STAT3 has been demonstrated to occur in many cancers and enhances tumour growth, migration, and invasion. Stimulation by cytokines, growth factors, and hormones triggers this activation by phosphorylating STAT3 at tyrosine 705. Novel imidazopyridine compounds were synthesized to evaluate the inhibition of STAT3 at Y705. Among the tested compounds, 16 reduced the level of phospho-STAT3, inhibited the downstream signalling cascade and subsequently attenuated the survival of hepatocellular carcinoma (HCC) cells. Further assays showed that the reduction effects of compound 16 on tyrosine 705 of STAT3 were attributed to up-regulation of protein tyrosine phosphatase SHP-1.

Total Synthesis and Biological Evaluation of Hybrubin A

Here, we report the first total synthesis of hybrubin A, a bipyrrole tetramic acid alkaloid representing a new carbon framework derived from convergent (truncated red cluster and exogenous hbn cluster) biosynthetic pathways. A highly convergent synthesis was developed, employing 4-methoxy-1,5-dihydro-2H-pyrrol-2-one (13) as a single starting material to provide hybrubin A in three steps from 13 and 20.8% overall yield. As no biological activity was prescribed to hybrubin A except for a lack of cytotoxicity, we further profiled this unique alkaloid across panels of discrete molecular targets. Interestingly, hybrubin A was found to be a ligand for a variety of GPCRs with a propensity for potent binding across therapeutically relevant adenosine receptors (A1, A2a, and A3) as well as a potent activity at a kinase, FLT3. This pattern of biological activity is distinct from other related prodigiosin natural and unnatural products and is even more intriguing in the absence of cytotoxicity.

Metal-Free and Versatile Synthetic Routes to Natural and Synthetic Prodiginines from Boron Dipyrrin

Prodiginines, as a family of bacterial alkaloids, possess a number of interesting biological activities. New, concise synthetic routes for the facile preparation of both synthetic and natural prodiginines in good yields have been developed, which use BODIPY functionalization reactions, such as condensation, nucleophilic substitution, and BF2 deprotection. This new metal-free synthetic method opens the door toward a wide variety of C-ring functionalized prodiginines, including those that are not possible to obtain through current synthetic methods, for their advanced biological activities.

Stereochemistry and Mechanism of Undecylprodigiosin Oxidative Carbocyclization to Streptorubin B by the Rieske Oxygenase RedG

The prodiginines are a group of specialized metabolites that share a 4-methoxypyrrolyldipyrromethene core structure. Streptorubin B is a structurally remarkable member of the prodiginine group produced by Streptomyces coelicolor A3(2) and other actinobacteria. It is biosynthesized from undecylprodigiosin by an oxidative carbocyclization catalyzed by the Rieske oxygenase-like enzyme RedG. Undecylprodigiosin derives from the RedH-catalyzed condensation of 2-undecylpyrrole and 4-methoxy-2, 2′-bipyrrole-5-carboxaldehyde (MBC). To probe the mechanism of the RedG-catalyzed reaction, we synthesized 2-(5-pentoxypentyl)-pyrrole, an analogue of 2-undecylpyrrole with an oxygen atom next to the site of C-C bond formation, and fed it, along with synthetic MBC, to Streptomyces albus expressing redH and redG. This resulted in the production of the 6′-oxa analogue of undecylprodigiosin. In addition, a small amount of a derivative of this analogue lacking the n-pentyl group was produced, consistent with a RedG catalytic mechanism involving hydrogen abstraction from the alkyl chain of undecylprodigiosin prior to pyrrole functionalization. To investigate the stereochemistry of the RedG-catalyzed oxidative carbocyclization, [7′-2H](7′R)-2-undecylpyrrole and [7′-2H](7′S)-2-undecylpyrrole were synthesized and fed separately, along with MBC, to S. albus expressing redH and redG. Analysis of the extent of deuterium incorporation into the streptorubin B produced in these experiments showed that the pro-R hydrogen atom is abstracted from C-7′ of undecylprodigiosin and that the reaction proceeds with inversion of configuration at C-7′. This contrasts sharply with oxidative heterocyclization reactions catalyzed by other nonheme iron-dependent oxygenase-like enzymes, such as isopenicillin N synthase and clavaminate synthase, which proceed with retention of configuration at the carbon center undergoing functionalization. (Chemical Equation Presented).

Antimalarial activity of natural and synthetic prodiginines

Prodiginines are a family of linear and cyclic oligopyrrole red-pigmented compounds. Herein we describe the in vitro antimalarial activity of four natural (IC50 = 1.7-8.0 nM) and three sets of synthetic prodiginines against Plasmodium falciparum. Set 1 compounds replaced the terminal nonalkylated pyrrole ring of natural prodiginines and had diminished activity (IC 50 > 2920 nM). Set 2 and set 3 prodiginines were monosubstituted or disubstituted at either the 3 or 5 position of the right-hand terminal pyrrole, respectively. Potent in vitro activity (IC50 = 0.9-16.0 nM) was observed using alkyl or aryl substituents. Metacycloprodiginine and more potent synthetic analogues were evaluated in a P. yoelii murine patent infection using oral administration. Each analogue reduced parasitemia by more than 90% after 25 (mg/kg)/day dosing and in some cases provided a cure. The most favorable profile was 92% parasite reduction at 5 (mg/kg)/day, and 100% reduction at 25 (mg/kg)/day without any evident weight loses or clinical overt toxicity.

Role and substrate specificity of the Streptomyces coelicolor RedH enzyme in undecylprodiginine biosynthesis

The function of RedH from Streptomyces coelicolor as an enzyme that catalyses the condensation of 4-methoxy-2,2′-bipyrrole-5-carboxaldehyde (MBC) and 2-undecylpyrrole to form the natural product undecylprodiginine has been experimentally proven, and the s

A scalable process for the synthesis of the Bcl inhibitor obatoclax

Recently we created the novel indolylprodigiosin derivative 2 (obatodax) and demonstrated its ability to antagonize multiple members of the B-cell lymphoma (Bd) family of antiapoptotic proteins. The compound has shown potent anticancer activity in several animal tumor models. Obatodax is now in Phase 1b and 2 clinical trials directed against multiple hematologic and solid tumor malignancies. To support its clinical development, a new scalable synthesis was required. Obatodax has been prepared using a three-step synthesis, starting from commercially available 4-methoxy-3-pyrrolin-2-one. The reaction sequence involves a haloformylation reaction followed by a Suzuki cross-coupling reaction with an indole-2-boronic add. The synthesis is completed by an acid-mediated condensation with 2,4-dimethyl-1H-pyrrole.

METHODS FOR TREATING ARTHRITIS USING TRIHETEROCYCLIC COMPOUNDS

The present invention relates to methods for treating or preventing arthritis comprising administering a Triheterocyclic Compound. In one embodiment, the present invention relates to methods of using Triheterocyclic Compounds for treating or preventing rh