Tricyclic Carbazole Research Articles

A Cyclobutanol Ring-Expansion Approach to Oxygenated Carbazoles: Total Synthesis of Glycoborine, Carbazomycin A and Carbazomycin B

AbstractThe transition-metal-free total syntheses of the oxygenated carbazole natural products glycoborine, carbazomycin A and carbazomycin B are reported. The key step involves an NBS-mediated cyclobutanol ring expansion to 4-tetralones for the preparation of the tricyclic carbazole core.

Switching Prenyl Donor Specificities in Squalene Synthase-Like Aromatic Prenyltransferases from Bacterial Carbazole Alkaloid Biosynthesis.

Lavanduquinocin (LDQ) is a potent neuroprotective carbazole alkaloid from Streptomyces species that features a rare cyclic monoterpene/cyclolavandulyl moiety attached to the tricyclic carbazole nucleus. We elucidated the biosynthetic logic of LDQ by enzymatically reconstituting the total biosynthetic pathway and identified the genes required for generating the cyclolavandulyl moiety in LDQ based on mutagenetic analysis, including a cyclolavandulyl diphosphate synthase gene ldqA and a squalene synthase-like aromatic prenyltransferase gene ldqG. LdqG is homologous to carbazole prenyltransferases, NzsG and CqsB4, discovered from the biosynthetic pathways of two bacterial carbazoles, neocarazostatin and carquinostatin. Based on analysis of the sequences and modeled protein structures, further in vitro and in vivo site-directed mutagenetic analyses led to identification of two residue sites, F53 and C57 in NzsG vs I54 and A58 in LdqG, which play crucial roles in governing the prenyl donor specificities toward cyclolavandulyl, dimethylallyl, and geranyl diphosphates. By applying this knowledge in strain engineering, prenyl donor delivery was rationally switched to produce the desired prenylated carbazoles. The study provides an opportunity to rationally manipulate the prenylation modification to carbazole alkaloids, which could influence the biological activities by increasing the affinity for membranes as well as the interactions with cellular targets.

Antimicrobial Chlorinated Carbazole Alkaloids from the Sponge‐Associated Actinomycete Streptomyces diacarniLHW51701

Main observation and conclusionFour new chlorinated carbazole alkaloids, chlocarbazomycins (CCBs) A—D, were isolated from sponge associated bacterium Streptomyces diacarni LHW51701. Their structures were elucidated via spectroscopic techniques (including HRESIMS, 1D & 2D NMR), and X‐ray crystallographic analysis. Structurally, the 4‐chloro coupled with 3‐methoxyl substituents in the tricycle nucleus of CCBs A—D and the N‐methoxyl group of CCB‐D are rare in naturally occurred tricyclic carbazole alkaloids. Moreover, CCBs A—D do not bear the typical C1 para‐alkyl and C2 meta‐methyl side chains of bacterial tricycle carbazoles, suggesting a novel mechanism of aromatic ring formation in biosynthesis. The biological evaluation showed that CCB‐C possessed inhibitory activities against pathogenic microorganisms including methicillin‐resistant Staphylococcus aureus (MRSA), Mycobacterium smegmatis, Bacillus mycoides, and Candida albicans.

Recent Advances in the Biosynthesis of Carbazoles Produced by Actinomycetes.

Structurally diverse carbazole alkaloids are valuable due to their pharmaceutical properties and have been isolated from nature. Experimental knowledge on carbazole biosynthesis is limited. The latest development of in silico analysis of the biosynthetic gene clusters for bacterial carbazoles has allowed studies on the biosynthesis of a carbazole skeleton, which was established by sequential enzyme-coupling reactions associated with an unprecedented carbazole synthase, a thiamine-dependent enzyme, and a ketosynthase-like enzyme. This review describes the carbazole biosynthetic mechanism, which includes a key step in enzymatic formation of a tricyclic carbazole skeleton, followed by modifications such as prenylation and hydroxylation in the skeleton.

Enzymatic Reconstitution and Biosynthetic Investigation of the Bacterial Carbazole Neocarazostatin A.

Tricyclic carbazole is an important scaffold in many naturally occurring metabolites, as well as valuable building blocks. Here we report the reconstitution of the ring A formation of the bacterial neocarazostatin A carbazole metabolite. We provide evidence of the involvement of two unusual aromatic polyketide proteins. This finding suggests how new enzymatic activities can be recruited to specific pathways to expand biosynthetic capacities. Finally, we leveraged our bioinformatics survey to identify the untapped capacity of carbazole biosynthesis.

Synthesis and Pharmacological Evaluation of Tricyclic Carbazole Annulated with Substituted Benzothiazole-2-Amine Under Microwave Irradiation

Synthesis and Pharmacological Evaluation of Tricyclic Carbazole Annulated with Substituted Benzothiazole-2-Amine Under Microwave Irradiation

Anti-tuberculosis activity and structure–activity relationships of oxygenated tricyclic carbazole alkaloids and synthetic derivatives

A series of 49 oxygenated tricyclic carbazole derivatives has been tested for inhibition of the growth of Mycobacterium tuberculosis and a mammalian cell line (vero cells). From this series, twelve carbazoles showed a significant anti-TB activity. The four most active compounds were the naturally occurring carbazole alkaloids clauszoline-M (45), murrayaline-C (41), carbalexin-C (27), and the synthetic carbazole derivative 22 with MIC90 values ranging from 1.5 to 3.7μM. The active compounds were virtually nontoxic for the mammalian cell line in the concentration range up to 50μM.

A ThDP-dependent enzymatic carboligation reaction involved in Neocarazostatin A tricyclic carbazole formation.

Although the biosynthetic pathway of Neocarazostatin A (1) has been identified, the detailed enzymatic reactions underlying the assembly of the carbazole ring still remain largely unknown. We demonstrate here that NzsH, a putative thiamine diphosphate dependent enzyme, can catalyze an acyloin coupling reaction between indole-3-pyruvate and pyruvate to generate a β-ketoacid intermediate. Our findings thus shed light on further characterization of the unusual biosynthetic pathway of the bacterial tricyclic carbazole alkaloids.

Biosynthesis of Neocarazostatin A Reveals the Sequential Carbazole Prenylation and Hydroxylation in the Tailoring Steps

Neocarazostatin A (NZS) is a bacterial alkaloid with promising bioactivities against free radicals, featuring a tricyclic carbazole nucleus with a prenyl moiety at C-6 of the carbazole ring. Here, we report the discovery and characterization of the biosynthetic pathway of NZS through genome mining and gene inactivation. The invitro assays characterized two enzymes: NzsA is a P450 hydroxylase and NzsG is a new phytoene-synthase-like prenyltransferase (PTase). This is the first reported native PTase that specifically acts on the carbazole nucleus. Finally, our invitro reconstituted experiment demonstrated a coupled reaction catalyzed by NzsG and NzsA tailoring the NZS biosynthesis.

ChemInform Abstract: Biological Potential of Carbazole Derivatives

AbstractReview: 157 refs.

9-(4-Bromobutyl)-9H-carbazole

In the title compound, C16H16BrN, the tricyclic carbazole system is essentially planar (r.m.s. deviation of all non-H atoms = 0.010 Å). The dihedral angle between the two outer carbazole rings is 1.1 (3)°. There are no directional inter­molecular contacts in the crystal packing.

Transition Metals in Organic Synthesis, Part 95:¹ First Total Synthesis of the 1,7-Dioxygenated Carbazole Alkaloids Clausine Q and Clausine R

The sequence of palladium(0)-catalyzed amination and palladium(II)-catalyzedoxidative formation of the biaryl bond provides a direct route tothe 1,7-dioxygenated tricyclic carbazole alkaloids clausine Q andclausine R.

Carvedilol dihydrogen phosphate propan-2-ol solvate from powder diffraction data

In the cation of the title compound, C24H27N2O4 +·H2PO4 −·C3H8O [systematic name: 3-(9H-carbazol-4-yl­oxy)-2-hydr­oxy-N-[2-(2-methoxy­phen­oxy)eth­yl]propan-1-aminium dihydro­gen phosphate propan-2-ol solvate], the mean planes of the tricyclic carbazole system and the benzene ring form a dihedral angle of 42.00 (16)°. In the crystal structure, classical inter­molecular O—H⋯O and N—H⋯O hydrogen bonds link the cations, anions and solvent mol­ecules into layers parallel to the ac plane.

9-Hexyl-3-iodo-9H-carbazole

In the title mol­ecule, C18H20IN, the tricyclic carbazole system is essentially planar with the two outer rings forming a dihedral angle of 0.43 (8)°. The crystal packing exhibits no short inter­molecular contacts.

First total synthesis of the biologically active 2,7-dioxygenated tricyclic carbazole alkaloids 7-methoxy-O-methylmukonal, clausine H (clauszoline-C), clausine K (clauszoline-J) and clausine O

Using the iron-mediated arylamine cyclization as the key step we have achieved a short and highly efficient access to the biologically active 2,7-dioxygenated tricyclic carbazole alkaloids 7-methoxy-O-methylmukonal, clausine H (clauszoline-C), clausine K (clauszoline-J) and clausine O.