Mitsuru Ohkubo

Practical synthesis of indolopyrrolocarbazoles

Abstract A practical method for the synthesis of an indolo[2,3-a]pyrrolo[3,4-c]carbazole ring system is described. The method involves two key processes: a coupling reaction between indole and substituted methylmaleimide portions using lithium hexamethyldisilazide (LiHMDS) as a base, and the oxidative cyclization of bisindolylmaleimide with palladium (II) chloride. We applied this method to the synthesis of arcyriaflavin B ( 5 ), C ( 6 ) and D (7).

MK-5108, a Highly Selective Aurora-A Kinase Inhibitor, Shows Antitumor Activity Alone and in Combination with Docetaxel

Aurora-A kinase is a one of the key regulators during mitosis progression. Aurora-A kinase is a potential target for anticancer therapies because overexpression of Aurora-A, which is frequently observed in some human cancers, results in aberrant mitosis leading to chromosomal instability and possibly tumorigenesis. MK-5108 is a novel small molecule with potent inhibitory activity against Aurora-A kinase. Although most of the Aurora-kinase inhibitors target both Aurora-A and Aurora-B, MK-5108 specifically inhibited Aurora-A kinase in a panel of protein kinase assays. Inhibition of Aurora-A by MK-5108 in cultured cells induced cell cycle arrest at the G2-M phase in flow cytometry analysis. The effect was confirmed by the accumulation of cells with expression of phosphorylated Histone H3 and inhibition of Aurora-A autophosphorylation by immunostaining assays. MK-5108 also induced phosphorylated Histone H3 in skin and xenograft tumor tissues in a nude rat xenograft model. MK-5108 inhibited growth of human tumor cell lines in culture and in different xenograft models. Furthermore, the combination of MK-5108 and docetaxel showed enhanced antitumor activities compared with control and docetaxel alone–treated animals without exacerbating the adverse effects of docetaxel. MK-5108 is currently tested in clinical trials and offers a new therapeutic approach to combat human cancers as a single agent or in combination with existing taxane therapies. Mol Cancer Ther; 9(1); 157–66

Synthesis of NB-506, A new anticancer agent

Abstract 6-N-formylamino-12,13-dihydro-1,11-dihdyroxy-13-(β-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole-5,7(6H)-dione (NB-506, 2), a derivative of the naturally occurring antitumor compound, BE-13793C (3), is a new indolopyrrolocarbazole anticancer agent which potently inhibits topoisomerase 1. The synthesis of NB-506 was accomplished starting from dibromomaleimide 4 and indole compound 5. The key step, a glycosylation of indolocarbazole, was precisely studied to develop a practical synthesis method using KOH as a base.

Synthesis of Dissymmetric Indolocarbazole Glycosides Using the Mitsunobu Reaction at the Glycosylation Step

Abstract A novel method for the synthesis of N-glycosylated dissymmetric indolo[2,3-a]pyrrolo-[3,4-c]carbazole derivatives was developed by applying the Mitsunobu reaction to the N-glycosylation reaction of substituted indole substrates.

In vivo Anti‐tumor Activity of a Novel Indolocarbazole Compound, J‐107088, on Murine and Human Tumors Transplanted into Mice

J‐107088 (6‐N‐(1‐hydroxymethyl‐2‐hydroxy)ethylamino‐12,13‐dihydro‐2,10‐dihydroxy‐13‐(β‐D‐glu‐copyranosyl)‐5H‐indolo[2,3‐a]‐pyrrolo [3,4‐c]carbazole‐5,7(6H)‐dione) is a derivative of NB‐506, an indolocarbazole compound previously reported as an anti‐tumor agent targeting topoisomerase L The optimal administration schedule of J‐107088 was found to be intermittent injections. The GID75 (75% growth inhibiting total dose) values of J‐107088 against LX‐1 lung cancer and PC‐3 prostate cancer when given by intermittent injection (twice a week for 2 consecutive weeks) were 200 and 15 mg/m2, respectively, whereas the 10% lethal dose (LD10) values of J‐107088 against LX‐1‐ and PC‐3‐bearing mice were 578 and 1200 mg/m2. The ratio of LD10/GID75 indicates the therapeutic window of an anti‐tumor agent. Although the ratios of doxorubicin, paclitaxel and cisplatin against PC‐3 were <0.3, <0.5 and <0.2, J‐107showed the widest therapeutic window among the anti‐tumor drugs tested. J‐107088 was also effective on cells that had acquired resistance related to P‐glycoprotein. Furthermore, J‐107088 was found to be highly effective in inhibiting proliferation of micro‐metastases of tumors to the liver in mice. Therefore, J‐107088 is considered to be a promising candidate as an anti‐tumor drug for treatment of solid tumors in humans.

Synthesis and biological activities of NB-506 analogues modified at the glucose group.

A new indolocarbazole compound, NB-506 (1), modified at the glucose group yielded a beta-D-glucopyranoside, J-107,088 (2), which showed potent anticancer activity. A beta-D-ribofuranoside, J-109,534 (3), was found to be 6 times more potent than J-107,088 at inhibiting topoisomerase I.

Synthesis and biological activities of NB-506 analogues: Effects of the positions of two hydroxyl groups at the indole rings.

In the course of a study of 6-N-amino-substituted analogues of NB-506 (1), a more potent anticancer drug, J-109,404 (2), in which the formyl group of NB-506 was replaced with a 1,3-dihydroxypropane group, was reported. A study of further modification in the positions of two hydroxyl groups at the indole rings of 2 resulted in the discovery of a 2,10-dihydroxy analogue, J-107,088 (3), which is a promising anticancer agent with a broader therapeutic window than J-109,404.

SOLID PHASE SYNTHESIS OF ARYL AND HETEROARYL AMINES USING THE CURTIUS REARRANGEMENT

Abstract An efficient method for the solid phase synthesis of secondary aryl amines and heteroaryl amines was developed. The key step was the formation of aryl or heteroaryl carbamates using the Curtius rearrangement of aryl carboxylic acids with Wang resin as a trapping hydroxyl group. N-alkylation reactions of resin-bound carbamates under the Mitsunobu condition or using sodium hydride gave secondary aryl or heteroaryl amines in good yields. The developed method can be applied in the preparation of libraries containing aryl and heteroaryl amine structures as a pharmacophore.

Synthesis and biological activities of topoisomerase I inhibitors, 6-N-amino analogues of NB-506

6-N-Amino analogues of NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione] (3b) were synthesized and tested with respect to topoisomerase inhibition, cytotoxicity and anticancer effects. Among them, a 1,3-dihydroxypropane analogue (J-109,404, 5t) showed more than ten times more potent anticancer activity in MKN-45 human stomach cancer cells implanted in mice than NB-506.