Anti-AIDS agents. 31. Synthesis and anti-HIV activity of 4-substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) thiolactone analogs

Four DCK-thiolactone analogs (3-6) were synthesized asymmetrically and evaluated for anti-HIV activity against HIV-1 replication in H9 lymphocyte cells. Based on the functionality on the thiolactonecoumarin nucleus, activity was in the order: methyl > H > propyl > benzyl. 4-Methyl-3',4'-di-O-(-)-camphanoyl-(+)-cis-khelthiolactone (4) exhibited extremely potent anti-HIV activity with EC50 and therapeutic index values of 0.00718 microM and > 21,300, respectively.     

Anti-AIDS agents. 32. Synthesis and anti-HIV activity of betulin derivatives

Eleven betulin derivatives were prepared and evaluated for anti-HIV activity in H9 lymphocytes. Compound 4 was found to be the most active with EC50 and TI values of 0.00066 microM and 21,515, respectively.     

Studies on anti-platelet agents. II. Synthesis and platelet-inhibitory activity of 5-methyl-4-(3-pyridyl)-2-(substituted benzimidazol-5-yl)imidazoles

A series of 5-methyl-4-(3-pyridyl)-2-(substituted benzimidazol-5-yl)imidazole derivatives was synthesized and tested for anti-platelet and vasodilatory activities. Some compounds were found to have potent activities and low acute toxicity. In particular, 5-methyl-4-(3-pyridyl)-2-(7-chloro-6-methoxy-2- methylbenzimidazol-5-yl)imidazole (26) and 5-methyl-4-(3-pyridyl)-2-(7-chloro-3-methoxy-2-methylbenzimidazol- 5-yl)imidazole (33) exhibited 63% or 51% inhibition at a dose of 10 mg/kg for anti-patelet activity ex vivo in rats, respectively, while they showed no toxicity even at 180 or 100 mg/kg, respectively. Compound 33 also exhibited potent vasodilatory activity (ED50 = 11 micrograms/ml). Enzyme studies on these imidazoles showed that the novel imidazoles inhibit some enzymes which are involved in the platelet aggregation cascade such as cyclooxygenase, phosphodiesterase (PDE), and thromboxane A2 synthetase. The enzyme assay also suggested that the inhibitory activity on PDE may account for the vasodilatory activity of these imidazoles.     

Design of antineoplastic agents based on the "2-phenylnaphthalene-type" structural pattern. 4. Synthesis and biological activity of 2-chloro-3-(substituted phenoxy)-1, 4-naphthoquinones and related 5,8-dihydroxy-1,4-naphthoquinones

The intermediate in the preparation of 1,3,7, 10-tetrahydroxybenzo[b]naphtho[2,3-d]furan-6,11-dione (2), 2-chloro-5,8-dimethoxy-3-(3,5-dimethoxyphenoxy)-1,4-naphthoquinone (8h), and corresponding hydroxyl, methoxyl, and acetoxyl analogues was found to possess interesting inhibitory activities in a number of cytotoxic test systems. Activities were also noticed in some 5, 8-dihydroxy-1,4-naphthoquinone derivatives. A structure-activity discussion of compounds of this series is presented. The newly uncovered biological activity of 2-chloro-3-(substituted phenoxyl)-1, 4-naphthoquinones and 2,3-bis(substituted phenoxy)-1, 4-naphthoquinones may suggest an approach for the development of new classes of antineoplastic agents.     

Anti-hepatitis B virus activity and metabolism of 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine

2',3'-Dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine [L(-)Fd4C] was found to be at least 10 times more potent than beta-L-2',3'-dideoxy-3'-thiacytidine [L(-)SddC; also called 3TC, or lamivudine]against hepatitis B virus (HBV) in culture. Its cytotoxicity against HepG2 growth in culture was also greater than that of L(-)SddC (3TC). There was no activity of this compound against mitochondrial DNA synthesis in cells at concentrations upto 10 microM. The dynamics of recovery of virus from the medium of cells pretreated with equal drug concentrations were slower with L(-)Fd4C than with L(-)SddC (3TC). L(-)Fd4C could be metabolized to mono-, di-, and triphosphate forms. The degree of L(-)Fd4C phosphorylation to the 5'-triphosphate metabolite was higher than the degree of L(-)SddC (3TC) phosphorylation when equal extracellular concentrations of the two drugs were used. The apparent K(m) of L(-)Fd4C phosphorylated metabolites formed intracellularly was higher than that for L(-)SddC (3TC). This may be due in part to a difference in the behavior of L(-)Fd4C and L(-)SddC (3TC) towards cytosolic deoxycytidine kinase. Furthermore, L(-)Fd4C 5'-triphosphate was retained longer within cells than L(-)SddC (3TC) 5-triphosphate. L(-)Fd4C 5'-triphosphate inhibited HBV DNA polymerase in competition with dCTP with a Ki of 0.069 +/- 0.015 microM. Given the antiviral potency and unique pharmacodynamic properties of L(-)Fd4C, this compound should be considered for development as an expanded-spectrum anti-HBV drug.     

Semisynthetic cephalosporins. III. Synthesis and structure activity relationships of novel orally active 7-[4-hydroxy-3-(substituted methyl)phenyl]-acetamido-3-cephem-4-carboxylic acids

A family of novel optically active alpha-amino-3-substituted-methyl-4-hydroxy benzene acetic acids (3) have been prepared. A number of these amino acids were converted to a group of cephalosporins (12). Compound 12A showed the most interesting activity in vitro and in vivo, primarily against Gram-positive organisms and was shown to be well absorbed orally.     

Inactivation of S-adenosyl-L-homocysteine hydrolase and antiviral activity with 5',5',6',6'-tetradehydro-6'-deoxy-6'-halohomoadenosine analogues (4'-haloacetylene analogues derived from adenosine)

Treatment of a protected 9-(5, 6-dideoxy-beta-D-ribo-hex-5-ynofuranosyl)adenine derivative with silver nitrate and N-iodosuccinimide (NIS) and deprotection gave the 6'-iodo acetylenic nucleoside analogue 3c. Halogenation of 3-O-benzoyl-5,6-dideoxy-1, 2-O-isopropylidene-alpha-D-ribo-hex-5-enofuranose gave 6-halo acetylenic sugars that were converted to anomeric 1,2-di-O-acetyl derivatives and coupled with 6-N-benzoyladenine. These intermediates were deprotected to give the 6'-chloro 3a, 6'-bromo 3b, and 6'-iodo 3c acetylenic nucleoside analogues. Iodo compound 3c appears to inactivate S-adenosyl-L-homocysteine hydrolase by a type I ("cofactor depletion") mechanism since complete reduction of enzyme-bound NAD+ to NADH was observed and no release of adenine or iodide ion was detected. In contrast, incubation of the enzyme with the chloro 3a or bromo 3b analogues resulted in release of Cl- or Br- and Ade, as well as partial reduction of E-NAD+ to E-NADH. Compounds 3a, 3b, and 3c were inhibitory to replication of vaccinia virus, vesicular stomatitis virus, parainfluenza-3 virus, and reovirus-1 (3a < 3b < 3c, in order of increasing activity). The antiviral effects appear to correlate with type I mechanism-based inhibition of S-adenosyl-L-homocysteine hydrolase. Mechanistic considerations are discussed.     

Synthesis and biological evaluation of 4-chloro-3, 5-dinitrobenzotrifluoride analogues as antileishmanial agents

Desnitro analogues of 4-chloro-3,5-dinitrobenzotrifluoride (chloralin) (2), an in vitro microtubule inhibitor of several Leishmania species, have been synthesized from 2-halo-5-(trifluoromethyl)benzenesulfonyl chlorides 4 and 5. The analogues exhibited moderate to excellent activity when tested against Leishmania donovani amastigotes in vitro. Two representative compounds, 7f and 8, were tested against the Khartoum strain of L. donovani in a hamster model using chloralin (2) and Glucantime (one of the current therapeutics of choice in the treatment of Leishmania) as standards, the results of which will be discussed herein.     

Antitumor agents. 181. Synthesis and biological evaluation of 6,7,2',3',4'-substituted-1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic antitumor agents

A novel series of 6,7,2',3',4'-substituted-1,2,3,4-tetrahydro-2-phenyl- 4-quinolones were synthesized and evaluated for interactions with tubulin and for cytotoxic activity against a panel of human tumor cell lines, including ileocecal carcinoma (HCT-8), breast cancer (MCF-7), lung carcinoma (A-549), epidermoid carcinoma of the nasopharynx (KB), renal cancer (CAKI-1), and melanoma cancer (SKMEL-2). Most compounds (18, 20, 22-27) showed potent cytotoxic and antitubulin effects. The most active compounds (23, 26, 27) demonstrated strong cytotoxic effects with ED50 values in the nanomolar or subnanomolar range in almost all tumor cell lines. Three active racemates (20, 22, 25) were separated into the enantiomers, and generally, the optically pure (-)-isomers (20a, 22a, 25a) exhibited greater biological activity than the racemates or (+)-isomers. Cytotoxicity and antitubulin activity were closely correlated, with the most active compounds (23, 26, 27) having effects comparable to those of colchicine, podophyllotoxin, and combretastatin A-4.     

Studies on anti-inflammatory agents. V. Synthesis and pharmacological properties of 3-(difluoromethyl)-1-(4-methoxyphenyl)-5- [4-(methylsulfinyl)phenyl]pyrazole and related compounds

A series of novel 1,5-diphenylpyrazole derivatives bearing hydrophilic substituents was prepared. The anti-inflammatory and analgesic activities of these compounds were evaluated by using the adjuvant arthritis and Randall-Selitto assays in rats, and the structure-activity relationships were studied. The optimal compound was 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (10) with oral ED50 values of 0.31 and 2.6 mg/kg on adjuvant-induced arthritis and carrageenin-induced foot edema, respectively. Compound 10 showed analgesic activities not only toward inflamed paw but also toward normal paw (ED30 = 0.55 and 1.8 mg/kg, respectively) in the Randall-Selitto assay, and moreover, 10 was effective in the tail-pinch assay (ED50 = 21 mg/kg) similarly to morphine. The asymmetric synthesis and pharmacological properties of the enantiomers of 10 are also reported.     

Synthesis and antihypertensive activity of 4-(diazabicyclo[4.1.0]-heptenyloxy)benzopyran derivatives and their analogues

A series of 3,4-dihydro-3-hydroxy-4-[(5-oxo-3,4-diazabicyclo[4.1.0]hept- 2-en-2-yl)oxy]-2H-1-benzopyrans and their analogues were synthesized and evaluated on potassium channel opening and hypotensive activities. Compound (-)-13B with a (4-methyl-5-oxo-3,4-diazabicyclo[4.1.0]hept-2-en-2-yl)oxy group for the 4-position of the benzopyran ring was 3 times as potent as EMD 57283 (II), the lead compound, in hypotensive activity. The results would demonstrate that 5-oxo-3,4-diazabicyclo[4.1.0]hept-2-en-2-yloxy moieties are effective as the substituents at the 4-position of benzopyran-type potassium channel openers.     

Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine

A three-component library of compounds was prepared in parallel using multiple simultaneous solution-phase synthetic methodology. The compounds were biased toward opioid receptor antagonist activity by incorporating (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (a potent, nonselective opioid pure antagonist) as one of the monomers. The other two monomers, which included N-substituted or unsubstituted Boc-protected amino acids and a range of substituted aryl carboxylic acids, were selected to add chemical diversity. Screening of these compounds in competitive binding experiments with the kappa opioid receptor selective ligand [3H]U69,593 led to the discovery of a novel kappa opioid receptor selective ligand, N-?(2'S)-[3-(4-hydroxyphenyl)propanamido]-3'-methylbutyl?-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (8, RTI-5989-29). Additional structure-activity relationship studies suggested that 8 possesses lipophilic and hydrogen-bonding sites that are important to its opioid receptor potency and selectivity. These sites appear to exist predominantly within the kappa receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the mu receptor and an 18-fold increase in affinity for the kappa receptor relative to the mu-selective ligand, (+)-N-[trans-4-phenyl-2-butenyl]-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (5a). The degree of selectivity observed in the radioligand binding experiments was not observed in the functional assay. According to its ability to inhibit agonist stimulated binding of [35S]GTPgammaS at all three opioid receptors, compound 8 behaves as a mu/kappa opioid receptor pure antagonist with negligible affinity for the delta receptor.     

Chemistry of cephalosporin antibiotics. 28. Preparation and biological activity of 3-(substituted)vinyl cephalosporins

3-(Substituted)vinylcephem nuclei have been prepared by the reaction of 3-formylcephem derivatives with stabilized phosphoranes. Appropriate synthetic steps allowed preparation of a series of 3-ethoxycarbonylvinyl- and 3-carboxyvinylcephem derivatives bearing a variety of 7-acylamino functions. The phenoxyacetyl and thiopheneacetyl derivatives of the 3-cyanovinylcephem nucleus were also prepared. Although general gram-positive activity was comparable to cephalothin in many cases, against penicillin G resistant Staphylococcus aureus, the new cephalosporins were of low effectiveness. The 3-(substituted)vinyl cephalosporins had good activity against a number of gram-negative organisms. In some cases, this activity was excellent. The N-acetyl analogs had surprisingly good activity relative to N-acetyl-7-ACA. The phenylmalonoyl side-chain derivatives were shown to have an unusual antibacterial spectrum expansion (relative to previously known cephalosporins) to include activity against Serratia marcescens and Pseudomonas aeruginosa.     

Potential antitumor agents. 19. Multiply substituted 4'-(9-acridinylamino)methanesulfonanilides

A series of 42 multiply substituted 4'-(9-acridinylamino)methanesulfonanilides has been prepared and evaluated in the L1210 system. In addition to biologic activity changes resulting from altered agent lipophilic-hydrophilic balance variants containing both acridine 4-CH3 and 3-NH2, NHCOCH3 or NO2 substituents have reduced activity. Variants 3,6-disubstituted, using functions of differing electronic character, have depressed activity, suggesting that there is limited site bulk tolerance. Asymmetric 3,5-disubstitution should then be the preferred pattern; the 3-ND-5CH-3'-OCH variant is the most dose potent (optimum dose qd 1-5, 1.25 mg/kg/day) of the high activity agents of this series so far prepared.     

Synthesis and antibacterial activity of novel 7-(3-substituted-3 or 4-trifluoromethyl-1-pyrrolidinyl)-8-methoxyfluoroquinolones

The titled compounds were synthesized and evaluated for in vitro antibacterial activity. The (3R, 4S)-3-aminomethyl-4-trifluoromethyl derivative (S-34109) was confirmed to be optimal because of its superior activity against quinolone and methicillin-resistant Staphylococcus aureus and low side effect potential.     

New azole antifungals. 3. Synthesis and antifungal activity of 3-substituted-4(3H)-quinazolinones

A series of 92 azole antifungals containing an amido alcohol unit was synthesized. The nature and substitution of the amide portion was systematically modified in search of improved antifungal activity, especially against filamentous fungi. The compounds were tested in vitro against a variety of clinically important pathogens and in vivo (po) in a murine candidosis model. Thiazole and thiophene carboxamides carrying both a substituted phenyl ring and a small alkyl group were best suited for activity against filamentous fungi. In a subset of these compounds, the amide portion was conformationally locked by means of a pyrimidone ring and it was proven that only an orthogonal orientation of the phenyl ring yields bioactive products. A tendency to display long plasma elimination half-lives was observed in both series. Two compounds, 74 and 107, representative of the open and cyclic amides, respectively, were chosen for further studies, based on their excellent activity in in vivo murine models of candidosis and aspergillosis. This work describes the SARs found within this series. The next paper displays the results obtained in a related series of compounds, the quinazolinones.     

Synthesis and evaluation of 4-amino-substituted 7-methoxy (and 7-hydroxy)- 11-methyl (and 5,11-dimethyl)-10H-pyrido [2,3-b] carbazoles and 4-amino- substituted 11-methyl (and 5,11-dimethyl)-10H-pyrido[3',4':4,5] pyrrolo [3,2-g] quinolines, two new series related to antitumor ellipticine derivatives

2-Acetyl-4-chloro-3-lithiopyridine ethylene glycol ketal (6b) was reacted with 3-formyl-5-methoxy-1-methyl-indole (9) and 3-formyl-1-methyl-1H-pyrrolo [3,2-c] pyridine (12), giving the corresponding expected alcohols. Reduction of these intermediates with triethylsilane trifluoroacetic acid and subsequent cyclodehydration then led to 4-chloro-7-methoxy-10,11-dimethyl-10H-pyrido [2,3-b] carbazole (8a) and the corresponding 7-aza-analog (8b). The synthesis of 4-chloro-11-methyl (and 5,11-dimethyl)-10-unsubstituted derivatives of these two series was performed through an independent pathway, involving condensation of conveniently substituted 2-amino carbazoles (17) and 7-amino-5H-pyrido [4,3-b] indoles (18) with 5-(ethoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione, thermal cyclization of the resulting compounds with concomitant decarboxylation to the corresponding tetracyclic fused-4-quinolone systems and final chlorination with phosphorus oxychloride. Nucleophilic substitution of various 4-chloro derivatives was then easily performed in an excess of the required dialkylamino alkylamines at reflux and 4-amino substituted-7-hydroxy-10H- pyrido [2,3-b] carbazoles (25d-e) were obtained from 7-methoxy precursors (25a-b), by demethylation with boron tribromide in methylene chloride at -65 degrees C or with boiling 47% hydrobromic acid. Cytotoxicity determination of all new aminosubstituted derivatives and in vivo antitumor evaluation of the most active compounds clearly show that these two series of ellipticine analogs closely related to highly active products are devoid of antitumor properties in two experimental models shown to be sensitive to ellipticines. The place of the pyridinic nitrogen atom in these series has thus been demonstrated to play a crucial role in antitumor activity.     

Synthesis and biological activity of folic acid and methotrexate analogues containing L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid

Clinical and pathological features of 52 infants and children with atypical teratoid/rhabdoid tumor (ATT/RhT) of the central nervous system are defined. This tumor is typically misdiagnosed as a primitive neuroectodermal tumor (PNET) primarily because 70% of ATT/RhTs contain fields indistinguishable from classic PNETs. Separation of these two tumor types is crucial because the prognosis for ATT/RhT is given even when treatment includes surgery with or without radio and/or chemotherapy. These tumors are most common in infants less than 2 years of age. The cases described in this study arose in intracranially in all but one instance, although one-third had already spread throughout the subarachnoid space at presentation. Clinical signs and symptoms and radiological features do not distinguish ATT/RhTs from PNETs. The tumors are composed entirely (13%) or partly (77%) or rhabdoid cells. Seventy percent contains fields of typical PNET alone or in combinations with mesenchymal and/r epithelial elements. The immunohistochemical profile is unique: epithelial membrane antigen, vimentin, and smooth-muscle actin are positive in the majority of tumors and markers for germ-cell tumors are consistently negative. Abnormalities of chromosome 22 distinguish ATT/RhTs from PNETs, which typically display an i(17q) abnormality.