Biologically active carbazole derivatives: focus on oxazinocarbazoles and related compounds

Figures & data

Figure 1. Structures of oxazinocarbazole 2 and aminomethylated carbazoles 3–7.

Figure 2. Structures of tricyclic hydroxycarbazole and carbazolequinone derivatives 8–12.

Figure 3. Structures of pyrido and isoxazolocarbazolediones 13–16.

Figure 4. Structures of oxazinopyrimidocarboline derivatives 17 and 18.

Figure 5. Structures of N,N-bis(carbazolylmethyl)amines 19 and 20.

Figure 6. Structures of oxazinocarbazoles Ia–p, IIa–c, and IIIa–e.

Scheme 1. Synthesis of compounds 1–7.

Figure 7. SDS-PAGE of purified human protein kinase CK2 holoenzyme. About 15 µL of purified protein solution (0.25 µg/µL) were separated on a 12.5% acrylamide gel and stained with Coomassie Brilliant Blue G250. At the left, the apparent molecular mass of the marker proteins (lane 1) is given. Lane 2 shows the purified human CK2 enzyme holoenzyme (3.75 µg). The band below the CK2α belongs to the well-known degradation product of the α-subunit CK2α (amino acids 1–335), which is supposed to be enzymatically active and using occurs during purification33.

Table 1. Inhibition of human protein kinase CK2 by carbazole derivatives 10–16, Ia–p, IIa–c, and IIIa–e.

	hCK2
Compound	(%) Inhibition at 10 μM	IC50 (μM)
10	26	–
11	20	–
12	19	–
13	24^a,b	–
14	Not soluble	–
15	18^a,b	–
16	29^a,b	–
Ia	20	–
Ib	52	8.7
Ic	29	–
Id	18	–
Ie	26	–
If	21	–
Ig	58	14.0
Ih	14	–
Ii	17	–
Ij	09	–
Ik	15	–
Il	25	–
Im	26	–
In	07	–
Io	15	–
Ip	34	–
IIa	33	–
IIb	18	–
IIc	15	–
IIIa	17	–
IIIb	26	–
IIIc	25	–
IIId	31	–
IIIe	17	–
emodin	99	0.58

^aAll target compounds were tested at 10 µM, except for compounds 13, 15, and 16 (tested with saturated solutions appeared to be below 10 µM).

^bCompounds were tested in triplicates, except for compounds 13, 15, and 16 (only once experiment).

Table 2. Inhibition of human protein kinase CK2 by oxazinocarbazole 2 and aminomethylated carbazoles 3–7.

	hCK2
Compound	(%) Inhibition at 10 μM	IC50 (μM)
2	71	1.401
3	26	–
4	31	–
5	29	–
6	32	–
7	16	–

Figure 8. The ability of oxazinocarbazoles to induce IPC-81 leukemia cell death. IPC-81 cells were incubated with various concentrations of the compounds Ib, Ig, and 2, and apoptosis assessed by microscopic evaluation of leukemia cell morphology after 24 h.

Table 3. Antimicrobial activities (MIC µg/mL) of carbazole derivatives 8–10, 12, 17–20, Ic, Ik,l, Ip, and IIc.

	MIC (µg/mL)
Compound	Staphylococcus aureus CIP 103429	Enterococcus faecalis CIP 103214	Pseudomonas aeruginosa DSM 1117	Escherichia coli DSM 1103
8	32	32	>128	>128
9	64	32	>128	>128
10	16	16	>128	>128
12	>128	>128	>128	>128
17	>128	>128	>128	>128
18	>128	>128	>128	>128
19	>128	>128	>128	>128
20	>128	>128	>128	>128
Ic	>128	>128	>128	>128
Ik	>128	>128	>128	>128
Il	>128	>128	>128	>128
Ip	>128	>128	>128	>128
IIc	>128	>128	>128	>128

Table 4. Antiplasmodial activities (IC₅₀ nM) of carbazole derivatives 2, 8–10, 12, 17–20, Ib,c, Ig, Ik,l, Ip, and IIc.

	Plasmodium falciparum 3D7
Compound	IC50 (nM)
2	3380 ± 108
8	0675 ± 190
9	>4500
10	>4500
12	>4500
17	>4500
18	0551 ± 181
19	>4500
20	>4500
Ib	4244 ± 653
Ic	>4500
Ig	4131 ± 482
Ik	>4500
Il	>4500
Ip	0659 ± 180
IIc	0430 ± 390
Chloroquine	018.9 ± 0.53

Ermakova I, Boldyreff B, Issinger OG, Niefind K. Crystal structure of a C-terminal deletion mutant of human protein kinase CK2 catalytic subunit. J Mol Biol 2003;330:925–34

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