Synthesis and biological evaluation of phaitanthrin congeners as anti-mycobacterial agents.

Natural alkaloid, tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) and its analogues are found to exhibit potent anti-tubercular activity against MDR-TB. A novel class of indolo[2,1-b]quinazolinones have been synthesized to evaluate their anti-mycobacterial activity. Enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis is one of the key enzymes and has been validated as an effective anti-microbial target. In silico molecular docking study demonstrates that the synthesized compounds exhibit high affinity for the M. tuberculosis drug target InhA. Phaitanthrin is a natural product, which belongs to a family of tryptanthrin and exhibits structural similarity except at position 6. Phaitanthrin derivatives are prepared by modifying the keto functionality of tryptanthrin. These phaitanthrin congeners are found to display promising anti-tubercular activity.

Stereoselective synthesis of octahydrocyclohepta[c]pyran-6(1H)-one scaffolds through a Prins/alkynylation/hydration sequence.

Aldehydes undergo a smooth coupling with (E/Z)-non-3-en-8-yn-1-ol in the presence of 10 mol% of CuX and BF3·OEt2 under mild conditions to produce a novel class of octahydrocyclohepta[c]pyran-6(1H)-one derivatives in good yields with excellent diastereoselectivity through a sequential Prins/alkynylation/hydration. This is the first report on the termination of Prins cyclization with a tethered alkyne.

A novel Prins cascade process for the stereoselective synthesis of oxa-bicycles.

E- and Z-9-Methyldeca-3,8-dien-1-ols undergo smooth cyclization with aldehydes in the presence of 20 mol% AgSbF6 under extremely mild conditions to generate the corresponding oxa-bicycles in good yields with excellent selectivity. In fact, E-olefin affords the trans-product exclusively, whereas the Z-olefin gives the cis-product predominantly. In the case of E- or Z-8-methylnona-3,8-dien-1-ol, the product is formed via the termination of Prins cyclization with an allylic C-H bond through olefin migration. The termination of Prins cyclization with tethered olefin is an unprecedented reaction, which provides a useful motif of various natural products.

Tuning the reactivity of oxygen/sulfur by acidity of the catalyst in Prins cyclization: oxa- versus thia-selectivity.

An unprecedented oxa- versus thia-selectivity has been observed in Prins cyclization of 6-mercaptohex-3-en-1-ol with aldehydes. In the presence of a stoichiometric amount of strong Lewis or Brønsted acids, the reaction provides the hexahydro-2H-thieno[3,2-c]pyran skeleton predominantly via oxonium-Prins cyclization. In contrast, a catalytic amount of weak Lewis or Brønsted acids provides the hexahydro-2H-thiopyrano[4,3-b]furan preferentially through thionium-Prins cyclization.

Thia-prins bicyclization approach for the stereoselective synthesis of dithia- and azathia-bicycles.

A novel thia-Prins bicyclization approach has been developed for the first time for the synthesis of hexahydro-2H-thieno[3,2-c]thiopyran derivatives from the coupling of homoallylic mercaptans such as hex-3-ene-1,6-dithiol with various aldehydes using 10 mol % InBr3 in dichloromethane with high selectivity. In addition, the coupling of (E)-N-(6-mercaptohex-3-enyl)-4-methylbenzenesulfonamide with aldedydes affords the corresponding N-tosyloctahydrothiopyrano[4,3-b]pyrrole derivatives in good yields. This reaction is a stereoselective affording trans-fused product from E-homoallyllic mercaptan and cis-fused product from Z-homoallyllic mercaptan.

Friedel-Crafts Alkylation of Arenes Catalyzed by Ion-Exchange Resin Nanoparticles: An Expedient Synthesis of Triarylmethanes.

Friedel-Crafts alkylation of electron-rich arenes with aldehydes has been achieved in the presence of an active and selective Amberlyst-15 catalyst at the reaction temperature of 60 degrees C in solvent-free conditions. The catalyst exhibits a very high activity and offers the corresponding triarylmethanes in excellent yields with a high selectivity. The use of highly reactive and selective Amberlyist-15 makes this procedure simple, convenient, cost-effective, practical and environmentally friendly. This method provides an easy access to triarylmethanes in a single step using a readily available acidic ionic resin, which is a stable and easy to separate from the reaction mixture by a simple filtration technique.

Antitumor bicyclic hexapeptide RA-VII modulates cyclin D1 protein level.

A bicyclic hexapeptide, RA-VII or O-methyl deoxybouvardin, isolated from Rubia cordifolia, is known to inhibit protein biosynthesis in vitro and in vivo. We here demonstrate that the treatment of human colon cancer DLD-1 cells with RA-VII induces cell growth inhibition associated with a partial G1 arrest and a rapid decrease (below 2 h) in the level of cyclin D1 protein. Since cycloheximide, another protein synthesis inhibitor, neither decreased the amount of cyclin D1 in the cells nor arrested cells in G1 phase, it is unlikely that this RA-VII-induced reduction of cyclin D1 was fully dependent on its direct inhibitory effect of protein synthesis. Northern blot analysis revealed that RA-VII did not affect the level of cyclin D1 mRNA. Meanwhile, pre-treatment of cells with lactacystin, a proteasome inhibitor, abolished the RA-VII-induced decrease in cyclin D1. Moreover, RA-VII still decreased cyclin D1 protein in the presence of cycloheximide. These results indicate that the RA-VII-induced cyclin D1 decrease depends on cyclin D1 degradation via the ubiquitin-proteasome pathway and does not require additional protein synthesis. RA-VII might actively proceed the degradation process of cyclin D1 via the ubiquitin-proteasome pathway in DLD-1 cells.

Novel C-ring analogues of 20(S)-camptothecin-part-2: synthesis and in vitro cytotoxicity of 5-C-substituted 20(S)-camptothecin analogues.

A series of 5-C-substituted 20(S)-camptothecin analogues were synthesised and evaluated their in vitro anti-cancer activity. Several of these analogues have showed excellent activity against human tumor cell lines.

Polar substitutions in the benzenesulfonamide ring of celecoxib afford a potent 1,5-diarylpyrazole class of COX-2 inhibitors.

Several chemical modifications in the N(1)-benzenesulfonamide ring of celecoxib are presented. The series with a hydroxymethyl group adjacent to the sulfonamide was found to be the most potent modification that yielded many compounds selectively active against COX-2 enzyme in vitro.

In vitro cytotoxicity of 5-aminosubstituted 20(S)-camptothecins. Part 1.

A number of 5-aminosubstituted 20(S)-camptothecin analogues were prepared via semi-synthesis starting from 20(S)-camptothecin and 9-methoxy 20(S)-camptothecin. In vitro anti-cancer activity of these analogues was determined using 60 human tumor cell line assay. Although water solubility of most of these compounds was improved compared to 20(S)-camptothecin, their anti-cancer activity was considerably diminished. However, only smaller substituents such as methylamine or hydroxylamine as present in 8s and 8t, respectively, showed good activity with improved water solubility.

Novel C-ring analogues of 20(S)-camptothecin. Part 3: synthesis and their in vitro cytotoxicity of A-, B- and C-ring analogues.

Several 5-substituted alkoxy 20(S)-camptothecin analogues having A- and B-ring substituents were prepared via semi-synthesis. Most of these compounds were found to exhibit potent anti-cancer activity based on their in vitro cytotoxicity data obtained against human tumor cell lines.

Novel 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues as cytotoxic agents.

A series of 6,7-diphenyl-2,3,8,8a-tetrahydro-1H-indolizin-5-one analogues were synthesized and evaluated for cytotoxic activity against eight human cancer cell lines. Compounds 18, 21, 28, 29, 30 and 31 showed cytotoxic activity with GI(50) values in the range of 2.1-8.1 microM concentration. Among these, compounds 21 and 28 exhibited good pharmacokinetic properties. These compounds were further evaluated for their in vivo efficacy in modified hollow fibre assay (HFA).

Biological investigation and structure-activity relationship studies on azadirone from Azadirachta indica A. Juss.

Azadirone 1, a limonoidal constituent of Azadirachta indica is found to possess potent cytotoxic activity against a panel of human cancer cell lines in our in vitro studies. In vitro screening of a number of semi-synthetic analogues of 1 revealed that the alpha,beta-unsaturated enone moiety or its equivalent conjugated system in A-ring, C-7 acetyloxy/chloroacetyloxy or keto group in B-ring and the furan moiety are responsible for the activity of 1 and its analogues. Compound 1 and two of the semi-synthetic analogues 10 and 13 were found to possess good in vivo antitumor activity in modified hollow fiber animal models.

Synthesis and biological evaluation of [4-(2-phenylethenesulfonylmethyl)phenyl]-quinazolin-4-yl-amines as orally active anti-cancer agents.

A new series of [4-(2-phenylethenesulfonylmethyl)phenyl]quinazolin-4-yl-amines was prepared and tested for its in vitro cytotoxic activity against a panel of 12 human cancer cell lines. Compounds 9, 15, 24 and 31 showed good in vitro activity and were further tested for their in vivo efficacy in the HT-29 human colon adeno carcinoma xenograft model. Compound 9 exhibited promising activity in this model. Dose-response studies for this compound against HT-29 human colon adeno carcinoma xenografts at 100, 200 and 400mg/kg doses were performed.

Novel indolo[2,1-b]quinazoline analogues as cytostatic agents: synthesis, biological evaluation and structure-activity relationship.

In our endeavor to design and synthesize novel anticancer agents, a new series of indoloquinazoline compounds were prepared and tested initially for anticancer activity in vitro against a panel of human cancer cell lines. Most of these compounds exhibited cytotoxic activity in in vitro screens. Compounds were selected and further evaluated using a modified Hollow Fiber Assay for their preliminary in vivo activity against 12 cell lines implanted in the subcutaneous and intraperitoneal compartments in mice. The results indicate that these compounds may constitute a new class of anticancer agents.