Antonia Reho

Synthesis, in vitro and in vivo cytotoxicity, and prediction of the intestinal absorption of substituted 2-ethoxycarbonyl-imidazo[2,1-b]benzothiazoles

The imidazobenzothiazole compounds 3-17 together with the imidazobenzoxazole 18, and the imidazobenzoimidazole 19 were prepared and their cytotoxic activity evaluated at the National Cancer Institute (NCI) for testing against a panel of approximately 60 tumor cell lines. Compounds 5, 7, 8, and 16 exhibited interesting in vitro cytotoxic activity. The most active imidazobenzothiazole derivative 8 was further evaluated as a cytotoxic agent in the hollow fiber assay and showed a score greater than the minimum values for xenograft testing together with a net cell kill. Comparison with the results displayed in the in vivo assay by standard antitumor drugs in clinical use revealed a significant in vivo activity of the benzothiazole compound. COMPARE analyses for compounds 4-19 against the NCIs standard agent database show poor or no correlation, and it might suggest for these compounds a mechanism of action unrelated to that of any known drug. Furthermore, the benzothiazole 8 did not show significant antitumor activity in a panel of two xenotransplanted tumors (i.e. colon and non-small cell lung tumors). By computing the polar surface area of compounds 3-19 with the MAREA computer program it was established that the most active compounds 5, 7, 8, and 16 should experience good intestinal permeability.

A rapid method for obtaining finasteride, a 5α-reductase inhibitor, from commercial tablets

To study the effects of allopregnanolone (AP) depletion on stress-induced dopamine changes in cortical dopamine, the 5alpha-reductase inhibitor finasteride on a gram-scale is required. Two procedures for the extraction of finasteride from tablets are outlined (method A and B). In method A, a suspension of powdered tablets was preliminary extracted with chloroform and the extracts dried and evaporated. The resulting residue was then purified on column chromatography. Method B involves a direct chromatographic separation of the powdered tablets. In terms of isolated yields, the second procedure works well, is cheaper, and less time-consuming. The efficiency of the method was tested by measuring progesterone, AP and THDOC content in plasma and cerebral cortex of rats. The protocol enables the prompt availability of sufficient amount of finasteride in experimental grade, useful in examining the role of endogenous cerebrocortical AP in brain homeostasis.

Reaction between 2,2′-dithiodianiline and activated alkynes. Synthesis of 4H-1,4-benzothiazines

By the title reaction acetylenic esters (2a–c), ketones (2d–g), and the nitrile (2h) gave in all cases the corresponding 4H-1,4-benzothiazines (3) together with other products whose nature depends on the alkyne used. Thus benzothiazoline and/or benzothiazole, benzothiazepine, and vinylsulphides were obtained in the representative cases (2c, f, h) studied in detail. Some of these latter compounds have been independently synthesised by reaction of 2-aminobenzenethiol with corresponding alkyne (2). In particular conditions by the reactions between 2,2′-dithiodianiline (1) and alkynes (2f, d) we isolated bisenamine compounds (19) and (20) respectively and their intermediacy in formation of the corresponding benzothiazines (3f) and (3d) was achieved. The mechanisms of the observed reactions are also suggested.

Rearrangement of N-acylspirocycloalkylbenzothiazolines. A new example of nitrogen→carbon acyl migration.

Abstract In boiling dimethyl sulfoxide (DMSO) the title compounds 1 rearrange to ω(benzothiazolyl)alkyl,aryl(or alkyl)ketones 3 .

REACTION BETWEEN 2,2′-DITHIODIANILINE AND FIVE-MEMBERED RING KETONES

Abstract The acid-catalyzed reaction between 2,2′-dithiodianiline (1) and various five-membered ring ketones yields, in the absence of oxygen, the expected 1,4-benzothiazines. On exposure to air, the latter undergo an autoxidation process, according to a previously described general pathway. From the autoxidation of 12, the hemithioketal 16 has been isolated, and its peculiar properties are discussed.

Synthesis of pyrrolo[2,1-c][1,4]benzothiazines by annellation of 3-alkoxycarbonylmethylene-4H-1,4-benzothiazines (β-enamine esters) with dimethyl acetylenedicarboxylate

The annellation of the benzothiazines (1a–c) with DMAD affords the corresponding pyrrolo[2,1-c][1,4]benzothiazines (5a–c) rather than pyrido[2,1-c][1,4]benzothiazines. Such structural assignments are based on spectroscopic and X-ray evidence

Lithiation α to heteroatoms: eliminative ring fission of heterocycles

The behaviour of some heterocycles, having two heteroatoms in a 1,4-relationship, towards lithium di-isopropylamide (LDA) has been examined. The dihydrobenzothiazines (2a–c) and (3b), morpholine (12), benzoxazine (14), oxathiane (16), piperazine (18), tetrahydroquinoxaline (20), 1,4-dithiane (25), and dihydrodioxine (27) undergo ready ‘eliminative ring fission.’ Very marked differences have been observed for unsubstituted and substituted derivatives. Whereas the dibenzoyltetrahydroquinoxaline (20) and the dioxine (27) readily react to give ring-opened products (21) and (30) respectively, substituted derivatives (22), (23), and (32) were found to be completely unreactive.

CHEMICAL BEHAVIOR OF SOME BENZ[b] INDENO[1,2-e] [1,4] THIAZINE DERIVATIVES

Abstract The study of the chemical behavior of some benz[b] indeno[1,2-e] [1,4] thiazine derivatives was accomplished. Different reactivities were observed for 4b,5-dihydrobenz[b]-indeno[1,2-e] [1,4] thiazine-10α(11H)-ol (3) and 5-ethyl-4b,5-dihydrobenz[b] indeno[1,2-e]-[1,4] thiazine-10α(11H)-ol (5); 3 is reoxidated to benz[b] indeno[1,2-e] [1,4] thiazine-10α(11H)-ol (2), while 5 undergoes transposition and oxidation to spiro[3-ethylbenzo-thiazol-2(3H), 1′-indan-2′-one] (6). Possible pathways for these transformations are discussed.

N-alkenyl acylketene S, N-acetals from 2,3-dihydro-1,3-benzothiazoles and carboxylic anhydrides. X-Ray molecular structure of 2-(butyrylmethylene)N-(cyclohex-1-enyl)-2,3-dihydro-1,3-benzothiazole

Depending on the reaction conditions or starting materials used, 2,3-dihydro-1,3-benzothiazoles 1 or their N-acyl derivatives 2 react with carboxylic anhydrides to yield the corresponding enamides 3 and/or N-alkenyl acylketene S,N-acetals 4. The structural assignments of these last compounds are based on spectroscopic data. X-Ray evidence for title compound 4c is also reported. A possible reaction pathway for formation of products 4 is suggested.