Acronycine

321.376

321.37

QE0G097358

403169

DTXSID0020026

C75297

Yellow needles from ethanol

38.8

3.67

Acronycine is a yellow powder. (NTP, 1992)

1.2±0.1 g/cm3

175-176 °C

489.8±45.0 °C at 760 mmHg

250.0±28.7 °C

1.612

less than 1 mg/mL at 64° F (NTP, 1992)

Water insoluble.

Amines, Phosphines, and Pyridines

Amines, like acronycine, are weak chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Flash point data for this compound are not available. It is probably combustible. (NTP, 1992)

Fires involving this compound can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this material in a refrigerator. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

The influence of three chemotherapeutic agents, acronycine, bleomycin and cytosine arabinoside, alone and combined with radiation, on cell cycle progression and viability of L-cells was examined. The percentages of cells in G1, S and (G2 + M)-phases as derived from pulse cytophotometric DNA distribution patterns were recorded as a function of exposure time. After 24-h treatment with 10 microgram/ml acronycine, 46.4% of cells were accumulated in (G2 + M)-phase compared to 12.1% in the controls. This accumulation was significantly enhanced by an irradiation with 150 rads of X-rays resulting in arresting 63.1% of cells in this phase. Similar findings were obtained after a 24-h treatment with 100 microgram/ml bleomycin. 54.4% of cells were arrested in (G2 + M)-phase by the chemical treatment alone, while the combined treatment, bleomycin and radiation, yielded an accumulation of 66.3% of cells in G2 + M. A 24-h exposure to 0.2 microgram/ml cytosine arabinoside (Ara-C) produced a reversible block of 72.8% of cells in S phase compared to 27.4% in the control cultures. This S block was less pronounced after the combined treatment (51.1%). Some implications of the results for combined therapy are discussed.

LD50 Mouse oral 522 mg/kg|LD50 Mouse intraperitoneal 613 mg/kg

A bioassay of acronycine for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Initially, groups of 35 rats of each sex were administered acronycine at one of two doses, either 7.5 or 15 mg/kg body weight, in a vehicle composed of 0.05% polysorbate 80 in phosphate-buffered saline. Control groups of each sex consisted of 10 untreated rats (untreated controls) and 10 rats injected with the vehicle (vehicle controls). Because of high mortality rates in the dosed animals, new dosed groups of 35 rats of each sex were started later at a dose of 3.75 mg/kg. Additional groups of 10 untreated and 10 vehicle controls of each sex were also started. The rats were administered the acronycine or the vehicle for 51 or 52 weeks, then observed for an additional 28-30 weeks. All surviving rats were killed at 80-82 weeks. Initially, groups of 35 mice of each sex were administered acronycine at one of two doses, either 12.5 or 25 mg/kg body weight, in a vehicle composed of 0.05% polysorbate 80 in phosphate-buffered saline. Control groups of each sex consisted of 10 untreated mice (untreated controls) and 10 mice injected with the vehicle (vehicle controls). Because of high mortality rates in the dosed animals, two additional dosed groups were started later: 35 mice of each sex at 6 mg/kg and 40 mice of each sex at 2 mg/kg, together with 10 untreated controls and 10 vehicle controls of each sex for the groups dosed at 6 mg/kg, and 20 untreated controls and 20 vehicle controls for the groups dosed at 2 mg/kg. Periods of administration of the chemical to the mice varied from 25 weeks to 92 weeks, depending on toxicity or length of time of survival. Surviving control animals were killed at 78-105 weeks. Acronycine was toxic to rats and mice of each sex at the doses used in this bioassay, as shown by the high mortality rates in all but the low-dose groups and by the lower mean body weights in dosed rats and mice at all doses throughout most of the bioassay. Because of this high number of deaths, time-adjusted statistics are used for the analyses of all incidences of tumors. In male rats, the dose-related trend in the mid-and high-dose groups for the incidence of osteosarcoma at all sites was significant (P=0.002) using the respective vehicle-control group (vehicle controls 0/8, mid-dose 13/30, high-dose 12/18). Comparisons of the individual groups with respective control groups were also significant for the mid-dose (P=0.022) and high-dose (P=0.002) groups, but not for the low-dose group. In female rats, osteosarcoma was observed only in 1/8 high-dose animals. Sarcomas and other related tumors of the peritoneum were observed in all three dosed groups of both male and female rats, but in none of the control groups (males: low-dose 5/30, mid-dose 3/26, high-dose 7/16; females: low-dose 1/35, mid-dose 5/30, high-dose 13/28). In both sexes, the dose-related trends were significant (males, P=0.006; females, P=0.002), and the comparison of the incidences in the high-dose females with the vehicle-control group was significant (P=0.016). None of the incidences in the individual dosed groups of males were significant when compared with vehicle controls. However, since the tumors were observed in all dosed groups but did not occur in historical-control animals at this laboratory, they are considered to be related to the administration of the chemical. In female rats, the incidence of all tumors of epithelial origin of the mammary gland was significant only at the low dose (low-dose vehicle controls 1/10, low-dose 22/35, P=0.004). Adenocarcinomas of the mammary gland were observed in seven low-dose, five mid-dose, and two high-dose female rats, but in no control females. The reverse dose relationship of both benign and malignant tumors was probably due to the higher number of early deaths which occurred in the high-dose group. In mice, the low survival in all dosed groups except the low-dose animals precluded an evaluation of the significance of the incidences of tumors. Lymphomas occurred in low-dose groups of both males and females; however, the incidence of lymphoma in different control groups was highly variable. The high incidence in the low-dose vehicle controls may have been due to a procedural problem associated with the possibility of transfer of tumor cells or oncogenic viruses during the intraperitoneal injection of the test chemical. It is concluded that under the conditions of this bioassay, the low survival of the dosed and control mice and the possible procedural problems associated with the intraperitoneal injection of the chemical did not allow a determination to be made of the carcinogenicity of acronycine in this species. In Sprague-Dawley rats, acronycine in the vehicle of 0.05% polysorbate 80 in phosphate-buffered saline was carcinogenic, producing tumors of the mammary gland in females, osteosarcomas in males, and sarcomas and other related tumors of the peritoneum in both males and females.

Originally isolated from an Australian plant, acronycine is an antitumor alkaloid with poor water solubility and low potency. The modest antitumor activity of this compound was markedly improved by the total synthesis of original analogs resulting in the selection of S23906-1, a diester derivative of 1,2-dihydrobenzo[b]acronycine. S23906-1 is characterized in vitro by a high potency in clonogenic assays and uncommon cell cycle pertubations. In vivo, this compound demonstrated a selectivity for human solid tumors as compared to murine transplantable tumors. The unique pharmacological profile of S23906-1 was particularly defined by a broad antitumor efficacy when administered i.v. or orally on aggressive orthotopic models of human lung, ovarian and colon models with comparable or better activity than clinically used anticancer drugs. The molecular mechanism of action of S23906-1 could involve DNA alkylation, modulation of cyclin E protein levels and inhibition of DNA synthesis leading to apoptosis. Ongoing preclinical toxicological studies will help to define the potential of this novel agent which is already considered as a valuable candidate for clinical studies.

Agents obtained from higher plants that have demonstrable cytostatic or antineoplastic activity. (See all compounds classified as Antineoplastic Agents, Phytogenic.)

... In vivo, this compound demonstrated a selectivity for human solid tumors as compared to murine transplantable tumors. The unique pharmacological profile of S23906-1 was particularly defined by a broad antitumor efficacy when administered i.v. or orally on aggressive orthotopic models of human lung, ovarian and colon models with comparable or better activity than clinically used anticancer drugs. The molecular mechanism of action of S23906-1 could involve DNA alkylation, modulation of cyclin E protein levels and inhibition of DNA synthesis leading to apoptosis.|With the goal of acquiring information that may prove of value in the development of structurally related compounds of greater clinical utility, mechanistic studies were performed with acronycine (I) and two semisynthetic derivatives, 2-nitroacronycine (II) and acronycine azine (III). These three substances demonstrated cytotoxic activity with several human tumor cell lines (breast, colon, lung, melanoma, KB-3, and drug-resistant KB-V1). Compounds II and III demonstrated greater activity than I, and more detailed studies were performed with cultured human breast cancer cells (UISO-BCA-1). Acronycine azine (III) induced the cells to accumulate in the G0/G1 phase of the cell cycle. It effectively inhibited the in vitro catalytic activities of partially purified DNA and RNA polymerases in a manner that was competitive with respect to DNA substrate. As judged by spectrophotometric titration, compound III interacted with calf thymus DNA, calf liver RNA, and a variety of single- and double-stranded (deoxy)ribonucleotides. Although no nucleic acid base specificity was discernable, this interaction appeared to be related to the cytotoxic mechanism of this dimeric substance. Monomeric compounds I and II did not interact with nucleic acids, but were effective inhibitors of DNA and RNA synthesis as judged by in vitro systems comprised of cultured UISO-BCA-1 cells or homogenates derived from these cells. The relative inhibitory activities of compounds I and II correlated with their cytotoxic activities suggesting a causal relationship. In addition, these two compounds induced cultured cells to accumulate in the phase of the cell cycle wherein the DNA content ranged from 2n-4n (S + G2/M), and inhibited in vitro DNA and RNA synthesis in a manner that was competitive with respect to nucleotide (TTP or UTP) substrate. Compounds I and II demonstrated greater cytotoxic activity with drug-resistant KB-V1 cells as compared with the parent (drug-sensitive) cell line, whereas this was not the case with compound III. Based on these results and previous literature reports, compounds I, II and III are likely to function by multiple mechanisms of action. However, it appears that alteration of nucleic acid metabolism is key to the activity of each of the substances.

ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits toxic fumes. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

Acronine