Synthesis of the acridone alkaloids glyfoline and congeners. Structure-activity relationship studies of cytotoxic acridones.

Glyfoline (4, 1,6-dihydroxy-10-methyl-2,3,4,5-tetramethoxyacridin-9-one) and its congeners were synthesized for evaluation of their cytotoxicity. A detailed structure-activity relationships (SAR) of these acridone derivatives were also studied. To study the SAR of glyfoline analogues, substituent(s) at C-1 and C-6 and at the heterocyclic nitrogen of glyfoline nucleus were modified. Nitro- and amino-substituted glyfoline analogues were also synthesized to study the effects of substituent(s) (electron-withdrawing vs electron-donating) on their cytotoxicity. These compounds were synthesized via the Ullmann condensation of anthranilic acids with iodobenzenes or 2-chlorobenzoic acids with aniline derivatives. The SAR studies showed that 1-hydroxy-9-acridones were more active than their 1-OMe derivatives against cell growth of human leukemic HL-60 cells in culture. Replacement of NMe of glyfoline with NH or N(CH2)2NEt2 resulted in either total loss or dramatic reduction of cytotoxicity. Glyfoline congeners with nitro function at the A-ring were inactive, while compounds with amino substituent were shown to be cytotoxic in vitro.

Syntheses and structure--activity relationships of novel apio and thioapio dideoxydidehydronucleosides as anti-HCMV agents.

On the basis of the fact that apio dideoxynucleosides, in which the furanose oxygen and the C2 of the 2,3-dideoxyribose are transposed, exhibited potent anti-HIV activity and 2',3'-dideoxy-2',3'-didehydronucleosides also showed potent anti-HIV activity, we synthesized apio dideoxydidehydronucleosides in which the oxygen atom and the double bond of the 2,3-dideoxy-2,3-didehydroribose are exchanged. The thioapio dideoxydidehydronucleosides were also synthesized since sulfur serves as a bioisostere of oxygen. Apio dideoxydidehydronucleosides 13a--f were synthesized starting from 1,3-dihydroxyacetone, utilizing phenylselenenyl chemistry as a key step. The ratio of the anomeric mixture was variable from 1:1 to 5:1 during the condensation of nucleosidic bases with the phenylselenyl acetate 11 in the presence of a Lewis acid. This is in contrast with other glycosyl donors such as 5-O-(tert-butyldiphenylsilyl)-2-phenylselenenyl-2,3-dideoxyribosyl acetate which shows excellent neighboring group effect (alpha:beta = 1:99). Thioapio dideoxydidehydronucleosides 22a,b were synthesized from the lactone 9 via thiolactone 17 as a key intermediate which was synthesized from dicyclohexylcarbodiimide coupling of the mercapto acid produced from the basic hydrolysis of thioacetate 16. The majority of apio analogues synthesized in this study exhibited moderate to potent anti-HCMV activity, among which the 5-fluorouracil derivative 13c was found to be the most potent against HCMV, while thioapio analogues showed no activity against HCMV. However, all synthesized compounds did not exhibit any significant activities against HIV-1, HSV-1, and HSV-2. The fact that apio dideoxydidehydronucleosides were active against HCMV suggests that the apio dideoxydidehydro sugar moiety can serve as a novel template for the development of new antiviral agents.

Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-beta-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships.

The syntheses of several 2'-halogeno-5-substituted-arabinofuranosylcytosines and -uracils are described, and relationships of structure to anti herpes virus activity in vitro were examined. Those arabinonucleosides containing the 2'-fluoro function exhibit, generally, more potent anti herpes virus (HSV) activity than do their 2'-chloro of 2'-bromo analogues. The importance of the fluorine in the 2'-"up" (arabino) configuration for enhancement of antiviral effectiveness is demonstrated by the superior activity of 2'-fluoro-5-iodo-ara-C [3a, FIAC] to that of 2'-fluoro-5-iodo-ribo-C. Of all the nucleosides tested herein, FIAC exhibited the most potent in vitro activity against HSV. 2'-Chloro-5-iodo- and -5-methyl-ara-C (3b and 4b) were 37 to greater than 500 times more effective in vitro against HSV type 2 than against type 1, suggesting that these latter derivatives might serve clinically as useful probes to distinguish between HSV types 1 and 2 in the diagnosis of HSV infections in man.

Structure-activity relationships of beta-D-(2S,5R)- and alpha-D-(2S,5S)-1,3-oxathiolanyl nucleosides as potential anti-HIV agents.

The beta-D-(2S,5R)- and alpha-D-(2S,5S)-1,3-oxathiolanylpyrimidine and -purine nucleosides with natural nucleoside configuration were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. The key intermediate 14, which was utilized for the synthesis of various nucleosides, was synthesized from D-mannose or D-galactose. Condensation of the acetate 14 with thymine, uracil, cytosine, and 5-substituted uracils and cytosines gave various pyrimidine nucleosides. The acetate 14 was also condensed with 6-chloropurine and 6-chloro-2-fluoropurine which were converted to various purine nucleosides. In the case of thymine, uracil, and 5-substituted uracil derivatives, most of the compounds did not exhibit any significant anti-HIV activity except 5-fluorouracil (alpha-isomer) derivative 55. Among 5-substituted cytosine analogues, 5-bromocytosine derivative (beta-isomer) 68 was found to be the most potent anti-HIV agent. In the case of purine derivatives, inosine analogue (beta-isomer) 78 was found to be the most potent anti-HIV agent in the 6-substituted purines and 2-amino-6-chloropurine derivative (beta-isomer) 90 showed the most potent activity in the 2,6-disubstituted purine series. The beta-isomers of 6-chloropurine (74), adenine (76), and N6-methyladenine (77) derivatives showed similar potencies against HIV-1, and the corresponding alpha-isomers also exhibited significant anti-HIV activity, although they were generally less potent than the beta-isomers.

Chemical sulfonation and anticoagulant activity of acharan sulfate.

Acharan sulfate is a glycosaminoglycan prepared from the giant African snail, Achatina fulica. This polysaccharide has a repeating disaccharide structure of -->4)-2-deoxy-2-acetamido-alpha-D-glucopyranose (1-->4)-2-sulfo-alpha-L-idopyranosyluronic acid (1-->). Its structure is related to heparin and heparan sulfate but is distinctly different from all known members of these classes of glycosaminoglycans. Because of its structural similarities to heparin, chemically modified acharan sulfate was studied to understand the chemical structure effected its anticoagulant activity. After de-N-acetylation, acharan sulfate was N-sulfonated using either chlorosulfonic acid-pyridine or sulfur trioxide-trimethylamine complex. The sulfate level in these products ranged from 22 to 24%(w/w), significantly less than that of heparin at 36%. The molecular weight of both N-sulfoacharan sulfates were comparable with that of heparin. In vitro anticoagulant activity assays showed that N-sulfoacharan sulfate derivatives were moderately active for the inhibition of thrombin and neither product showed any measurable anti-factor Xa activity. The differences in the activities of N-sulfoacharan sulfates produced by these two methods are probably ascribable to a small level of concomitant O-sulfonation obtained when using chlorosulfonic acid-pyridine.

Synthesis and antiviral activity of 2'-fluorohexopyranosyl nucleosides.

2'-Fluorohexopyranosyl nucleosides 1a and 1b which contained a bioisosteric double bond and a fluorine were synthesized in 12 steps, starting from D-galactose. During diethylaminosulfur trifluoride (DAST) fluorination, retention of stereochemistry was observed through the participation of methoxy or chloro group at the 6-position of the purine base. The final nucleosides 1a and 1b were found to be inactive against HIV-1 and HSV-1,2.

A synthetic study on cyclic phosphate derivatives of seconucleosides as potential antiviral agents (I). Synthesis of 3',5'-cyclic phosphates of 2'-substituted secouridines and secoribavirins.

The synthetic study of 3',5-cyclic phosphates of 2'-substituted 2',3'-secouridines and 2',3'-secoribavirins toward development of new antiviral agents is described. These cyclic phosphates were synthesized from their respective 4-nitrophenyl 3',5'-cyclic phosphate triesters. These triesters were prepared from the corresponding 2'-azido and 2'-bromo 2',3'-seconucleosides.

Synthesis of (-)-neplanocin A analogues as potential antiviral agents.

Based on (-)-neplanocin A with the 5'-hydroxyl substituted with fluoro, azido, or amino group, the corresponding xylo- and arabino derivatives were synthesized from D-ribose using the Mitsunobu reaction as a key step. None of the final nucleosides did show either significant antiviral activities or cytotoxicities.

Synthesis and biological activity of 5-hydroxy-4-quinolones and 5-methoxy-4-quinolones as truncated acridones.

A series of 5-hydroxy-4-quinolone (3) and 5-methoxy-4-quinolone (4) derivatives were synthesized as truncated acridone analogues and evaluated for antitumor, antiherpes and antituberculosis activities. Among them 5-hydroxy-8-methoxy-quinolone showed potent antitumor activity (IC50 = 17.7 microM for HL60) which was greater than that of acronycine. However, these compounds didn't show any significant antiherpes or antituberculosis activity.

Novel nucleosides with vinyl fluoride or vinyl bromide moiety as open-chain analogs of neplanocin A.

Novel nucleosides with vinyl fluoride and vinyl bromide were designed, synthesized and evaluated their antiviral activities against poliovirus, HSV, HIV, and HBV.

Synthesis and antiviral activity of D- and L-2'-azido-2',3'-dideoxy-4'-thiopyrimidine and purine nucleosides.

Novel D- and L-2'-azido-2',3'-dideoxy-4'-thionucleosides were synthesized starting from L- and D-xylose via D- and L-4-thioarabitol derivative as key intermediates and evaluated for antiviral activity, respectively. When the final nucleosides were tested against HIV-1, HSV-1, HSV-2, and HCMV, they were found to be only active against HCMV without cytotoxicity up to 100 micrograms/ml.

Design and synthesis of novel fluorocyclopropanoid nucleosides.

Novel fluorocyclopropanoid nucleosides were designed, synthesized and evaluated their antiviral activities against poliovirus, HSV, HIV, and HBV.

Synthesis of novel 3'-deoxy-3'-C-hydroxymethyl nucleosides with conformationally rigid sugar moiety as potential antiviral agents.

Based on the fact that the ring expanded 3'-C-hydroxymethyl analogue of oxetanocin A exhibited potent antiviral activity, two types of conformationally rigid 3'-C-hydroxymethyl derivatives in which 2'-hydroxyl group is linked to the 4'-position or to the 6'-position were synthesized starting from 1,2;5,6-di-O-isopropylidene-D-glucose, respectively.

Synthesis of novel D- and L-3'-deoxy-3'-C-hydroxymethyl nucleoside with exocyclic methylene as potential ribonucleotide reductase inhibitor.

D- and L-3'-Deoxy-3'-C-hydroxymethyl thymidine substituted with exocyclic methylene at 2'-position were synthesized, starting from D- and L-xylose as potential ribonucleotide reductase inhibitor, respectively, but they were found to be inactive against several tumor cell lines.

Structure-activity relationships of apio nucleosides as potential antiviral agents.

Several types of novel apio nucleosides were synthesized starting from 1,3-dihydroxyacetone and evaluated for antiviral activity. Among compounds tested, amino substituted apio dideoxynucleosides exhibited anti-HBV activity, while thioapio dideoxynucleosides were found to be active against HIV-1. Apio dideoxydidehydro nucleosides showed moderate to potent anti-HCMV activity, but their bioisosteric thioapio dideoxydidehydro nucleosides did not exhibit any significant antiviral activity.

Compliance in contact lens care.

Fifty patients who were originally fitted or refitted with daily-wear contact lenses at the UCLA contact lens service were interviewed on the nature of their care system compliance and hygiene. Good compliance was defined as meeting three preset, standardized criteria (hand washing before lens manipulation, correct use of a FDA-approved care system, and adherence to a daily-wear schedule). Twenty of our patients, or 40%, were found to be noncompliant. Noncompliance occurred more frequently in the 10 to 30 year age group and in those over 50 years of age and after lenses had been worn for more than 2 years. We also noted that patients with contact lens experience predating our contact lens care were more noncompliant as a group than those who only obtained contact lenses and care through our practice.

The use of spherical power effect bitoric rigid contact lenses in hospital practice.

In this retrospective study of astigmatic contact lens dispensing in the hospital setting, 680 patients were noted to have been dispensed new contact lens prescriptions over a specific 20-month period. Seventy-five patients (11%) received at least one astigmatic rigid or hydrogel contact lens. Forty-nine patients received at least one rigid astigmatic lens; 43 patients (63 eyes)--or about 87% of all rigid lens fittings--were dispensed spherical power effect (SPE) design rigid contact lenses. We find that we usually prescribe bitoric rigid lenses with the flatter (longer) meridian of the lens base curve about 0.50 diopters steeper than the flattest (longest) corneal meridian. Mean diameter was 9.3 mm, and about 80% of lenses were made from rigid gas permeable materials. The majority of patients were successful from a clinical perspective, with most attaining visual acuity equal to or better than with maximum spectacle correction, and with good comfort and physiological results.

Corneal abrasion associated with contact lens correction of keratoconus--a retrospective study.

BACKGROUND: Corneal abrasion is a frequently encountered complication of contact lens wear, but we are not aware of any previous study of relative frequency comparing keratoconic to nonkeratoconic patients. METHODS: We retrospectively studied the incidence of corneal abrasion during 2 months of contact lens practice. RESULTS: 784 contact lens-related patient visits (494 total patients); patients were assessed by 3 optometrists and 13 abrasions (11 patients) were diagnosed. Only the total number of individual patients and the first abrasion for each patient were statistically considered; the overall frequency of abrasion was therefore 11/494 (2.3%)/2 months. The frequency of abrasion was 5/68 (7.4%)/2 months for keratoconic patients and 6/426 (1.4%)/2 months for nonkeratoconic patients and this difference was significant (chi 2 test: p < 0.01). Among nonkeratoconic patients, the frequency of abrasion was 2/246 (0.8%)/2 months with hydrogel contact lens wear and 4/178 (2.2%)/2 months with rigid gas permeable (RGP) contact lens wear, but this difference did not achieve significance (chi 2 test: p = 0.10). IDENTIFIED RISK FACTORS INCLUDED: Contact lens wear; a torn lens and chemical keratitis for hydrogel lens wearers; an adherent "bound" lens and keratoconus for rigid lens wearers. CONCLUSION: Keratoconus appears to be a statistically significant risk factor for corneal abrasion among contact lens wearers.

Synthesis and antiviral activity of apio dideoxy nucleosides with azido or amino substituent.

Novel apio dideoxynucleosides with azido or amino or amino substituent were synthesized starting from 1,3-dihydroxyacetone utilizing an acid-catalyzed 1,4-conjugated addition as a key step and evaluated for antiviral activity. Unfortunately, they were found to be neither active against HIV-1, HSV-1,2 and poliovirus nor toxic.

Synthesis and antiviral activity of L-2'-deoxy-2'-up-fluoro-4'-thionucleosides.

L-2'-Deoxy-2'-up-fluoro-4'-thionucleosides were efficiently synthesized from D-xylose via L-4-thioarabitol derivative as a key intermediate and evaluated for antiviral activities against HIV-1, HSV-1,2 and HBV.