Antitumor agents. 16. Steroidal alpha-methylene-gamma-lactones.

Several novel steroidal alpha-methylene-gamma-lactones and related derivatives have been synthesized as potential steroid alkylating antitumor agents. The synthesis of these compounds involved the convenient Reformatsky-type reaction between ethyl-alpha-(bromomethyl)acrylate and the proper steroidal ketones. In vitro assay for the cytotoxicity of these compounds against the growth of tissue culture cells originating from human epidermoid carcinoma of the larynx (H.Ep.-2) has shown significant activity. Cytotoxicity was improved at least sixfold with the introduction of lipophilic steroidal character. Preliminary in vivo tumor assay also indicated that these compounds were active against Walker 256 carcinosarcoma in rats and were inactive against both L1210 lymphoid leukemia and Ehrlich ascites carcinoma in mice. However, the simple alpha-methylene-beta,beta-dicarbethoxy-gamma-butyrolactone significantly inhibited Ehrlich ascites tumor growth.     

Relative effectiveness of some compounds for the control of cisplatin-induced nephrotoxicity

Several procedures which have been reported as effective for the control of cisplatin induced nephrotoxicity were compared in the Sprague-Dawley rat using the same dose of cisplatin. The treatments examined were based on the use of sodium thiosulfate, sodium diethyldithiocarbamate (DDTC), glutathione (GSH), sodium N-methyl-D-glucamine dithiocarbamate (NaG) and S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721). The differences in the effectiveness of the procedures were assessed using BUN and serum creatinine values, histopathological examination, body weight changes, and renal platinum levels as indices. The effect of such treatments on the antineoplastic activity of cisplatin were examined with both the Walker 256 carcinosarcoma in the rat and the L1210 murine leukemia in mice. Under the conditions used, GSH was found to be more effective than the other nucleophiles in protecting against the nephrotoxicity of cisplatin while providing the least amount of interference with the antitumor activity as measured against the Walker 256 carcinosarcoma and the L1210 murine leukemia. Simultaneous i.v. administration of cisplatin and any of the sulfur-containing nucleophiles leads to a significant protection against the nephrotoxicity but reduced the anti-neoplastic activity of cisplatin when measured against the Walker 256 carcinosarcoma.     

Carbonyl derivatives of tilorone. Part 2: On the cancerostatic activity of carbonyl derivatives of tilorone (author's transl)]

A series of carbonyl derivatives of tilorone was synthetized by reaction with appropriate amino compounds, mainly hydrazines and hydrazides. The condensation products obtained were tested for cancerostatic activity against the murine leucaemia L 1210 and the Walker carcinosarcoma of the rat. Only three of the substances under investigation (1a, 5, 13) proved active against the Walker carcinosarcoma, one of which (5) being comparable to tilorone. No activity against L 1210 was observed, even tilorone exerted no effect. The reduction in activity against the Walker carcinosarcoma which resulted from the carbonyl substitution might be caused by a decrease in the ability to intercalate into DNA.     

Carbamoyl mycophenolic acid ethylester, an oral antitumor agent.

Several derivatives of mycophenolic acid (MA) were tested for their antitumor activity against leukemia L-1210 when administered orally and carbamoyl mycophenolic acid ethylester (CMAE) was selected as the most active antitumor agent in these tests. An oral administration of CMAE also inhibited the growth of Ehrlich solid carcinoma, NF sarcoma, myeloma X-5563 and sarcoma 180 in mice. In comparison with antitumor activity of MA, the improvement in activity of CMAE against leukemia L-1210 and Ehrlich solid carcinoma was indeed remarkable, CMAE seems to be less immunosuppressive than MA.     

N-甲基异靛兰的抗肿瘤作用

N-甲基异靛兰(代号靛Ⅲ),为靛玉红的类似物,对小鼠Lewis肺癌及大鼠Walker256有明显抑瘤作用,但对小鼠白血病L₁₂₁₀。无效。对小鼠Lewis肺癌的疗效靛Ⅲ至少相当靛玉红的8倍。对狗的毒性靛Ⅲ比靛玉红高1倍多,主要毒性表现为胃肠道反应。该药无论腹腔注射或口服均可抑制[³H]-TdR掺人大鼠Walker 256瘤细胞DNA。     

Studies on antitumor activities and pulmonary toxicity of pepleomycin sulfate (NK631) (author's transl)]

The antimicrobial and antitumor activities, and the pulmonary toxicity of pepleomycin (NK631) were studied in comparison with bleomycin (BLM). NK631 showed a broad antimicrobial spectrum against gram positive and gram negative bacteria equally to BLM, and its activity was about twice higher than BLM. NK631 showed higher activity on cultured HeLa S3 cells and higher antitumor effect on the transplanted tumors of Ehrlich solid carcinoma in mice, AH66 and AH66F ascites hepatoma in rats, and lower antitumor effect on Ehrlich ascites carcinoma in mice than BLM. Similarly to BLM, NK631 did not show satisfactory activity on L1210 leukemia in mice. NK631 showed marked effect on chemically induced squamous cell carcinoma, spontaneous lymph sarcoma of a dog, human and dog gastric cancer heterotransplanted in nude mice equally to BLM. Furthermore NK631 exhibited remarkably higher antitumor activity on lymph node metastasis of AH66 ascites hepatoma of rats and chemically induced gastric carcinoma of rats than BLM. Pulmonary toxicity of NK631 was low as 1/3 in incidence and 1/4 in grade of the BLM in old mice system. This trend was confirmed by chemical analysis of hydroxyproline in lung.     

Synthesis of 2,8-disubstituted imidazo[1,5-a]pyrimidines with potent antitumor activity

Seventeen 1,2,3,4-tetrahydroimidazo[1,5-a]pyrimidine derivatives bearing electron-withdrawing substituents were designed and synthesized by novel ring closure as potential antitumor agents. They were screened for their activities against mouse leukemia L1210 and human oral epidermoid carcinoma KB cell lines, and relationships of structure and antitumor activity in vitro are discussed. It was found that 8-thiocarbamoyl-1,2,3,4-tetrahydroimidazo[1, 5-a]pyrimidin-2(1H)-thione (8c) exhibited activity comparable to that of 5-fluorouracil against both L1210 and KB cells. The existence of both 2-thioxo and 8-substituent with a thioxo group in the molecule is crucial for the cytotoxicity against L1210 and KB cells. A novel procedure for introduction of a double bond between C-3 and C-4 in 8c was developed. Introduction of the 3,4-double bond increased the activity against L1210, but against KB cells the activity decreased by 4-fold. Cytotoxicity of compounds 8c and 8-thiocarbamoyl-1,2-dihydroimidazo[1,5-a]pyrimidin-2(1H)-thione (11c) against human solid tumor and leukemia cell lines was further evaluated. The saturation of the 3,4-double bond led to a significant increase in cytotoxicity against tumor cell lines tested.     

新抗癌有效成分海南粗榧内酯(Hainanolide)结构的研究

自海南粗榧树皮中分离出两种新的化合物即海南粗榧内酯和海南粗榧内酯醇,海南粗榧内酯是一种新抗癌有效成分。动物试验结果表明对L₆₁₅、S₁₈₀、Lewis肺癌P₃₈₈和L₁₂₁₀均显活性。根据X-衍射分析、核磁共振谱、红外光谱、紫外光谱、旋光光谱和质谱等证明海南粗榧内酯是一种新的结构类型的抗癌化合物,其结构式为Ⅰ。海南粗榧内酯醇的结构与海南粗榧内酯的结构很相似,其结构的研究正在进行中。     

Antitumor effects of biologic reducing agents related to 3,4-dihydroxybenzylamine: dihydroxybenzaldehyde, dihydroxybenzaldoxime, and dihydroxybenzonitrile

This report describes a structure-activity analysis of isomers of three classes of dihydroxybenzene derivatives, including dihydroxybenzaldoxime, dihydroxybenzaldehyde, and dihydroxybenzonitrile. These derivatives were examined for their effect on ribonucleotide reductase activity, macromolecular synthesis, cell growth, and in vivo antitumor activity against the L1210 murine leukemia. One of the compounds studied exhibited significant antitumor activity against the growth of L1210 leukemia cells. A comparison of the various analogues revealed a possible correlation for 3,4-dihydroxybenzaldoxime between its potent inhibitory effect toward ribonucleotide reductase activity (IC50 = 38 microM) and its superior L1210 antitumor activity [percent increased life span (% ILS) = 100].     

一些植物成分对实验肿瘤的作用

观察了18个植物成分对S180、Lewis肺癌、B16黑色素瘤、Ehrlich腹水癌、白血病P388、L1210和L615等小鼠肿瘤的疗效。以白血病P388和L1210最为敏感,L615最不敏感。此外,试验了高三尖杉酯碱、美登素、羟基喜树碱和长春新碱对Friend白血病的疗效,仅高三尖杉醋碱有明显疗效。部分样品还观察了对~3H标记的前体参入肿瘤细胞核酸和蛋白质的影响。     

Antineoplastic agents LXIV: 1,4-Bis(2'-chloroethyl)-1,4-diazabicyclo[2.2.1]heptane dihydrogen dimaleate

The 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo[2.2.1]heptane dication (II) exhibits remarkable antineoplastic activity. Detailed evaluation of several dianion derivatives showed a curative response level against the murine P-388 lymphocytic leukemia, colon 26, CD8F1 mammary, and the Walker 256 carcinosarcoma (rat) tumor systems. In addition, significant cancer chemotherapeutic activity was found against the murine L-1210 lymphoid leukemia, colon 38, and B16 melanocarcinoma tumor systems. The bicyclo dication (II) first was isolated, evaluated, and stored as the diperchlorate derivative (IIa). Because of the promising anticancer activity of IIa, procedures were developed for obtaining other anion derivatives for comparative biological purposes. Several naturally occurring substances were evaluated, and the dihydrogen dimaleate derivative (IIi) obtained by an ion-exchange technique was the most suitable.     

A new antitumor antibiotic, FR-900482. III. Antitumor activity in transplantable experimental tumors

FR-900482 (4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7, O10,12]tetradeca-2,4,6-triene-8-ylmethyl carbamate), a new antibiotic with antitumor activity was isolated from fermentation broth of Streptomyces sandaensis. Its antitumor activities were studied and compared with that of mitomycin C (MMC) in animals. FR-900482 in doses of 0.32 approximately 10 mg/kg (ip) prolonged the life of mice bearing ascitic P388, L1210, B16, MM46, Ehrlich or EL4 tumors and rats bearing ascitic AH130 or AMC60 tumors. FR-900482 in doses of 5.6 approximately 18 mg/kg (iv) inhibited human LX-1, MX-1, SC-6 and LC-6 tumors xenografted sc in nude mice. FR-900482 was more effective than or equally effective to MMC in all the tumors used. FR-900482 was ineffective against cyclophosphamide-resistant P388, but was effective against MMC- or vincristine-resistant P388. The results suggest that FR-900482 may have clinical potential.     

Isolation and properties of valanimycin, a new azoxy antibiotic

Valanimycin, a new azoxy antibiotic, was isolated from culture broths of a streptomycete. Valanimycin is an unstable oil at room temperature and active against some Gram-positive and Gram-negative bacteria, mouse leukemia L1210 cells in cultures, and prolongs the life span of mice inoculated with Ehrlich carcinoma or L1210.     

Studies on the mechanism of action of LS 1727, a nitrosocarbamate of 19-nortestosterone

LS 1727, a nitrosocarbamate of 19-nortestosterone, was active against lymphoid, antimetabolite-sensitive, cell lines in vitro especially L1210 and Ehrlich ascites tumour lines. It was less effective against alkylating agent-sensitive lines such as the Walker 256 carcinosarcoma. These results suggested a possible antimetabolite mode of action but LS 1727 had no effect on deoxy-or ribonucleotide pool sizes in L1210 cells. Studies on macromolecular synthesis showed an early inhibition of DNA synthesis whilst RNA and protein synthesis continued for 24-48 hours. This was reminiscent of a classic alkylating agent-like effect. In vivo studies with specific alkylating agent-sensitive, or antimetabolite-sensitive tumours showed no antitumour activity although significant inhibition of Ehrlich ascites tumour cell growth was observed at high doses. In vitro cytotoxicity studies showed LS 1727 to be inactivated in the presence of mouse, rat and dog liver supernatants. This would explain the poor antitumour effects in vivo compared with the in vitro observations. Because LS 1727 is a nitrosocarbamate its possible mutagenic activity was investigated. LS 1727 was highly mutagenic but this property was also lost in the presence of a rat liver microsomal fraction. Although an effective cytotoxic agent in vitro LS 1727 is only effective in vivo at toxic doses.     

Adozelesin,a selected lead among cyclopropylpyrroloindole analogs of the DNA-binding antibiotic,CC-1065

Summary Adozelesin (U-73975) is a potent synthetic cyclopropylpyrroloindole (CPI) analog of the cytotoxic DNA-binding antibiotic, CC-1065. In contrast to the natural product, adozelesin and related CPI analogs do not cause delayed death in non-tumored mice. Adozelesin, selected from a series of analogs for its superior in vivo antitumor activity and ease of formulation, is highly active when administered i.v. against i.p.- or s.c.-implanted murine tumors, including L1210 leukemia, B16 melanoma, M5076 sarcoma, and colon 38 carcinoma, and produces long-term survivors in mice bearing i.v.-inoculated L1210 and Lewis lung carcinoma. Modest activity is shown against the highly drug-resistant pancreas 02 carcinoma. Adozelesin is also highly effective against human tumor xenografts s.c.-implanted in athymic (nude) mice, including colon CX-1 adenocarcinoma, lung LX-1 tumor, clear cell Caki-1 carcinoma, and ovarian 2780 carcinoma. Its broad spectrum of in vivo activity compares favorably with three widely used antitumor drugs, i.e. cisplatin, cyclophosphamide, and doxorubicin. Adozelesin appears to be more effective than these drugs in the treatment of very resistant tumors such as s.c.-implanted mouse B16 melanoma, pancreatic 02 carcinoma, and human colon CX-1 and human lung LX-1 tumor xenografts. Based on its high potency and high efficacy against a broad spectrum of experimental tumors, adozelesin was chosen for clinical investigation and development.     

Beta-[1-Phenyl-5-bis(beta-chloroethyl)-amino-benzimidazolyl-(2)]-DL-alanine (ZIMET 3164): an immunosuppressant without marked anti-cancer effect

ZIMET 3164 inhibited the growth of sarcoma 180 P, sarcoma 180 G, and Walker 256 carcinosarcoma, but was unable to prolong the survival time of mice bearing Ehrlich ascites carcinoma or the leukaemias L 1210 and LAJ I to a worthwhile extent. The primary and secondarantly suppressed in mice. The drug exerted maximum effect when given on days--2 to +2 relative to antigenic stimulus. Administration exclusively prior to immunization induced only moderate immunosuppression while injection afterwards failed to affect the primary response at all, suggesting that the drug interfers with the afferent limb of immune response. In general, ZIMET 3164 proved to be half as effective as cyclophosphamide, but more effective than chlorambucil.     

Antineoplastic and biochemical properties of arylsulfonylhydrazones of 2-formylpyridine N-oxide.

The structural parameters necessary for the antineoplastic potency of a new class of anticancer agents, arylsulfonylhydrazones of 2-formylpyridine N-oxide, were examined in mice bearing Sarcoma 180 ascites cells. The findings indicated that (a) replacement of the pyridine ring with benzene, quinoline, or isoquinoline resulted in loss of activity (b) movement of the formylhydrazone side chain from the 2 to the 3 or 4 positions of the pyridine N-oxide produced inactive agents (c) the pyridine N-oxide function was essential for anticancer activity, except for 4-substituted derivatives which were active without the N-oxide group, (d) replacement of the SO2 group by CO resulted in complete loss of activity, and (e) a carbon atom could be inserted between the SO2 and aryl ring with retention of anticancer potency. One of the most active members of this series, 1-oxidopyridine-2-carboxaldehyde p-toluenesulfonylhdrazone, exhibited antineoplastic activity against a broad spectrum of transplanted tumors including Sarcoma 180, Hepatoma 129, Ehrlich carcinoma, leukemia L1210, and a subline of Sarcoma 180 resistant to alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazones. This agent caused inhibition of thymidine-3H and uridine-3H incorporation into DNA and RNA, respectively, of Sarcoma 180 ascites cells; protein biosynthesis was relatively insensitive to the action of this compound.     

The antineoplastic activity of trimethylamine carboxyboranes and related esters and amides in murine and human tumor cell lines

Trimethylamine carboxyboranes including their esters and amides were shown to have antineoplastic activity in vivo against Ehrlich ascites carcinoma growth. The derivatization to the ester or amide did not necessarily improve activity. Cytotoxicity of the derivatives was observed against the growth of murine and human tumor cells. Selectivity was demonstrated by the boron derivatives in the human solid tumor screens. Almost all the compounds demonstrated cytotoxicity against single-cell suspension growths, eg Tmolt3, L1210, HeLa-S3. Selection of two compounds to examine their mode of action in L1210 lymphoid leukemia cells showed that the agents perferentially inhibited DNA synthesis followed by protein and RNA synthesis. The d(TTP) pools were markedly reduced because of inhibition of nucleotide kinase activity. The agents also inhibited regulatory enzymes in the de novo purine pathway and afforded DNA strand scission. These effects by the agents were probably additive to bring about tumor cell death.     

Synthesis and activities of antitumor agents.

N-(2-Chloroethyl)-N-nitrosocarbamoyl derivatives of glycosylamines have been prepared. Six N-(2-chloroethyl)-N-nitrosoureas, including three disaccharide derivatives, were submitted to a determination of antitumor activity. All the compounds tested exhibited strong antitumor activity against leukemia L1210 in mice.     

Rationale for the synthesis and preliminary biological evaluation of highly active new antitumor nitrosoureido sugars

Various new nitrosoureido derivatives of di- or trideoxy sugars were synthesized. The influence of the hydroxyl substitution pattern, the configuration at the anomeric center, and the absolute configuration of the sugar moiety on the antitumor activity of a series of nitrosoureido derivatives of di- and trideoxy sugars was studied. All compounds showed a very significant activity in vivo against L1210 leukemia, B16 melanocarcinoma, and Lewis lung carcinoma. Methyl 3-[3-(2-chloroethyl)-3-nitrosoureido]-2,3-dideoxy-alpha-D-arabino- hexopyranoside, 24 (NSC 609224), was found to be the most active compound. When treated with 24 (NSC 609224) at 20 mg/kg on day 1, at least 90% of the L1210 leukemia and B16 melanocarcinoma bearing mice showed a survival of over 60 days for a LD50 value for this compound of 42 mg/kg.