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Reaction of 5-methyl-, 5-bromo-, and 5-iodoisatins with phosphoryl chloride gave the corresponding 2,8-disubstituted indolo[2,1-b]quinazoline-6,12-diones in moderate yield. 5,7-Dichloroisatin failed to react with POCl 3 . Treatment of an equimolar mixture of isatin and 5-bromoisatin with POCl 3 afforded indolo[2,1-b]-quinazoline-6,12-dione (tryptanthrin), 2,8-dibromoindolo[2,1-b]quinazoline-6,12-dione, and two isomeric monobromo-substituted tryptanthrin derivatives, the 2-bromo isomer prevailing. R = H (a), Me (b), Br (c), I (d). Tryptanthrin (couroupitine) or indolo[2,1-b]quinazoline-6,12-dione [1] is an alkaloid isolated from Candida lipolytica microscopic fungi which proliferate in the presence of a large amount of L-tryptophan [2], from higher terrestrial indigo-containing plants of the families Couroupita [3], Polygonum, Isatis [4], etc., and recently from the marine bacteria Oceanibulbus indolifex gen. nov., sp. nov. [5]. This compound exhibits antifungal activity [3], inhibits growth of Mycobacterium tuberculosis [6], as well as of Trypanosoma brucei and Leishmania donoivani protozoa which induce dangerous diseases [7, 8], and displays anti-inflammatory [9] and cancer-preventive properties [10].Alkaloid IIa was previously synthesized in high yield [11] according to a simple one-step procedure based on reaction of accessible isatin (Ia) with phosphoryl chloride. The goal of the present work was to extend this procedure with a view to obtain biologically active derivatives of tryptanthrin and refine the scheme of transformations involved. For this purpose, we examined reactions of 5-methyl-, 5-bromo-, 5-iodo-, and 5,7-dichloroisatins with POCl 3 and determined the composition of product mixture formed from isatin and 5-bromoisatin under similar conditions. By heating 5-methylisatin (Ib) with POCl 3 in boiling toluene over a period of 2 h we obtained 2,8-dimethylindolo[2,1-b]quinazoline-6,12-dione (IIb) (Scheme 1) which was isolated from the reaction mixture in 37% yield as a yellow-green crystalline substance. Thus compound Ib relatively readily undergoes cyclization. The structure of IIb was confirmed by NMR and mass spectra. All signals in the NMR spectra of compound IIb were assigned using 1 H-1 H COSY, HSQC, and HMBC techniques, and the position of methyl groups in the tetracyclic skeleton was unambiguously determined.Likewise, 5-bromoisatin (Ic) was converted into 2,8-dibromoindolo[2,1-b]quinazoline (IIc) in 30%

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Mostotrin (MT), a novel compound, at least five orders of magnitude more soluble in water than its mother substance, was designed and synthesised from tryptanthrin (TR). Its structure was established by nuclear magnetic resonance and mass spectrometry data and confirmed by X-ray analysis, revealing that MT is a pentacyclic product with an additional pseudo-cycle formed with the participation of one intramolecular hydrogen bond. Antimicrobial activity and cytotoxic action against tumour cells in vitro, as well as anti-tumour effects, acute toxicity and anti-inflammatory activities in vivo, were evaluated. Antimicrobial properties of MT against Mycobacterium spp and Bacillus cereus ATcc 10702 appeared to be the same as that of TR, but against the other strains used it was weaker. Furthermore, MT exhibited 5-10 times higher cytotoxic activities against tumour cell lines HcT-116, МСF-7 and K-562 than TR, but was less toxic than TR (Ld 50 of MT was 375 mg/kg, while Ld 50 for TR was 75 mg/kg). Additionally, compounds MT and TR were studied in dNA binding tests. The quenching of its fluorescence on addition to DNA solution established MT to be capable of binding to dNA. Its anti-tumour action in vivo on mice with the ascitic form of Ehrlich carcinoma was promising, particularly with joint application of MT and the antitumour drug doxorubicin. In this model, the survival and life span for the doxorubicin and 1 co-treatment group were significantly higher compared to doxorubicin treatment alone. The compound MT showed a lower immunosuppressive effect than TR at the early stages of inflammation induced in mice by LPS from E. сoli (MT hardly inhibited the release of IL-1, IL-2, or INF-γ). These results demonstrated that MT is a perspective hit compound for drug development. In our opinion, further evaluation on the biological effects of MT and its synthetic analogues could lead to safer and more effective anti-tumour and anti-tuberculosis agents than TR itself. MT has also the prospect of application in combination with known anti-tumour drugs for the treatment of oncological diseases.

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